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Complications of cirrhosis review
- 2. Outline • Portal hypertension • Ascites • Hepatic encephalopathy • Hepatorenal syndrome • Hypoalbuminemia and coagulopathy • Hepatocellular carcinoma • Prognostic Tools
- 4. Definition • Diffuse fibrosis following hepatocyte destruction and nodular regeneration • Multiple causes – All may lead to cirrhosis • Asymptomatic (compensated) • Symptomatic (decompensated) – portal hypertension – hepatic failure
- 5. The Natural History of cirrhosis Decompensation: •Variceal hemorrhage •Ascites •Encephalopathy •Jaundice D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217-231.
- 6. Liver insufficiency Variceal hemorrhage Decompensated Cirrhosis Ascites Encephalopathy Jaundice Portal hypertension SBP HRS Compensated Cirrhosis 5- 7% per year Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency
- 7. Natural History of Cirrhosis Stage Definition 1-year mortality Median Survival 1 Compensated without varices 1% >12 years 2 Compensated with varices 3% 3 Decompensated with ascites without variceal hemorrhage 20% ~2 years 4 Decompensated with/out ascites with variceal hemorrhage 57% D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217-231.
- 8. Clinical Presentation • Symptoms – Anorexia – Weight loss – Generalized weakness – Easy fatigability – Nausea – Vomiting – Diarrhea • Exam Findings – Spider angiomatas – Palmar erythema – Gynecomastia – Testicular atrophy – Leuconychia – Parotid gland hypertrophy – Dupuytren’s contractures – Clubbing – Jaundice Asymptomatic
- 10. Arroyo, V. & Fernández, J. Nat. Rev. Nephrol. 2011 Mechanisms Leading to Circulatory & Renal Dysfunction in Cirrhosis
- 11. 6040 80 100 120 140 160 0 40 60 80 20 200 100 Months Probability of survival All patients with cirrhosis Decompensated cirrhosis 180 Gines et. al., Hepatology 1987;7:122 Median survival ~ 9 years Median survival ~ 9 years Median survival ~ 1.6 years Median survival ~ 1.6 years Decompensation shortens survival
- 12. Venous Anatomy
- 13. Cirrhotic Liver
- 14. Pressure Measurements Portal Venous Pressure (PVP) Normal = 5-10 mm Hg Hepatic Venous Pressure Gradient (HVPG) = portal venous pressure - hepatic venous pressure or RA pressure Normal = 1-5 mm Hg PORTAL HTN
- 15. • HVPG ≥6 mm Hg • HVPG ≥10mm Hg – clinically significant • HVPG ≥12 mmHg, risk of variceal bleeding and the development of ascites • HVPG >20 mmHg – bleeding unlikely to respond to conventional therapy Definition of Portal Hypertension
- 16. Pathophysiology Portal Hypertension • Increased intrahepatic vascular resistance – Fixed component • Sinusoidal fibrosis • Compression by regenerative nodules – Functional component • Vasoconstriction – Deficiency in intrahepatic NO – Enhanced activity of vasoconstrictors
- 17. Classification Type Examples • Prehepatic Portal or splenic vein thrombosis Presinusoidal Schistosomiasis • Intrahepatic Sinusoidal Cirrhosis Postsinusoidal Veno-occlusive disease • Posthepatic Hepatic vein thrombosis Constrictive pericarditis
- 18. Varices: Portosystemic Collateral Formation • Esophageal varices • Gastric varices • Intraabdominal varices • Caput medusa • Rectal varices
- 19. Variceal Bleeding 35-80% 25-40% 50-70% Survival Death Rebleed 30-50% 70%
- 20. Varices • Common lethal complication • ~ 50% of patients with cirrhosis • More likely to bleed in more decompensated disease – 40% of Child A – 85% of Child C Practice Guidelines: Am J Gastroenterol. 2007;102:2086-2102
- 21. % Patients with varices 100 60 40 20 0 Overall n=494 Child A n=346 Child B n=114 80 Child C n=34 Large Medium Small Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72 Prevalence and Size of Esophageal Varices in Patients with Newly-Diagnosed Cirrhosis
- 22. LaPlace’s Law T = wall tension P1= intravariceal pressure P2 = esophageal lumen pressure r = vessel radius W = wall thickness T = (P1-P2) x (r/W)
- 23. Variceal Bleed: Risk Factors • High Gradient • Large esophageal varices • Endoscopic features – red wale markings – cherry red signs
- 24. Varices • All patients with new dx of cirrhosis should undergo EGD to screen for varices • High risk for bleeding: – Childs B/C (more evidence of decompensation) – Large varices – Red wale markings
- 25. Varices • Primary prophylaxis (never bled) – If no varices: no need for nonselective B blocker – If small varices: no long term evidence to use B blocker unless red signs present – If large varices: • High risk patient (red wale, childs B/C): B blocker (nadolol/ propranolol) or prophylactic banding • Low risk patients: B blocker – Titrate B blocker to max tolerated dose
- 26. Got one for you…Variceal Bleed • Blood transfusion: Target Hgb=8 • Antibiotics: norfloxacin, IV cipro, ceftriaxone (probably best) • Vasopressin, telipressin, octreotide, vapreotide x 3-5 days – Splanchnic vasoconstriction, reduced portal flow • EGD within 12 hours – Banding(almost always) or sclerotherapy (rare)
- 27. Variceal Bleed: When Banding Fails • Balloon Tamponade (Blakemore / Minnesota tube) temporizing measure for up to 24 hours • TIPS
- 28. After the Bleed • Secondary prophylaxis – All patients who have has a variceal bleed – Combination of B Blocker and serial banding – Continue banding (usually outpt) until varices are eradicated
- 29. Take Home: Varices • All patients with cirrhosis should be screened with EGD • Primary prophylaxis – Large varices / decompensated patients : usually nonselective B blocker – Banding and “sicker” patients • Variceal bleed: abx, octreotide, Hgb 8,scope with banding – Blakemore/TIPS when in trouble • Secondary prophylaxis – Combination B blocker / banding to eradication
- 30. Ascites
- 31. ASCITES
- 32. Definition • Fluid within the peritoneal cavity • Occurs in 50-60% of patients with cirrhosis over 10-15 years • Mixture of liver and intestinal lymph
- 33. Cirrhosis Heart failure Peritoneal tuberculosis Cirrhosis is the Most Common Cause of Ascites Others •Pancreatic •Budd-Chiari syndrome •Nephrogenic ascites Peritoneal malignancy CIRRHOSIS IS THE MOST COMMON CAUSE OF ASCITES 85% 33
- 34. Ultrasound
- 35. Pathophysiology Elevated Hydrostatic Pressure •Cirrhosis •Congestive heart failure •Constrictive pericarditis •Hepatic outflow block Decreased Oncotic Pressure •Nephrotic syndrome •Protein-losing enteropathy •Malnutrition •Cirrhosis Peritoneal Fluid Production > Resorption •Infections (bacterial, tuberculosis, fungal) •Neoplasms
- 36. Hepatic Sinusoid • Unlike other capillaries, normal hepatic sinusoids lack a basement membrane. • The sinusoidal endothelial cells themselves contain large fenestrae (200-400 nm in diameter) • These two features make the normal hepatic sinusoid very permeable with movement of fluid depending mostly on hydrostatic pressure • Normal portal sinusoid pressure is 3-4 mmHg 36
- 37. THE PERMEABILITY OF THE HEPATIC SINUSOID VARIES IN HEALTH AND DISEASE In cirrhosis, the hepatic sinusoid is LESS leaky The Permeability of the Hepatic Sinusoid Varies in Health and Disease Hepatocyt es The normal sinusoid is “leaky” Sinusoid Sinusoid fibrous tissue deposition “capillarization” of sinusoid no basement membrane 37
- 38. Clinical Presentation • Abdominal distention • Bulging flanks • Shifting dullness • Fluid wave • Fluid detected on US or CT scan
- 39. Total Protei n (SAAG = serum albumin - ascitic albumin) ≥1.1 <1.1 <2.5 -Cirrhosis -Acute Liver Failure -Alcoholic Hepatitis -Massive Hepatic Mets -Nephrotic syndrome -Myxedema ≥2.5 -CHF -Constrictive Pericarditis -Budd-Chiari -Venoocclusive Disease -Peritoneal Carcinomatosis -TB Peritonitis -Pancreatic Ascites -Chylous Ascites -Serositis 39 Serum-Ascites Albumin Gradient
- 40. Treatment of Ascites • Usually responds to Na restriction and diuretics – When SAAG >1.1 • Dual diuretics: – Furosemide AND Spirololactone • Single daily dosing (40/ 100) • Na restriction – <2000mg/day • Fluid restriction is usually NOT necessary
- 41. Patients with Refractory Ascites Have Worse Survival than Patients with Diuretic-Responsive Ascites Survival probability 1.0 .8 .6 .4 .2 0 120 24 4836 60 8472 Refractory ascites Non refractory ascites p<0.00 1 Months Salerno et al., Am J Gastroenterol 1993; 88:514
- 42. In refractory ascites… • AVOID – ACE inhibitors / angiotensin receptor blockers • Blood pressure / adverse renal effects – Propranolol • Blood pressure / circulatory dysfunction during LVP • Renal function – Consider risks benefits – NSAIDS
- 43. With Large / Tense ascites • Therapeutic paracentesis followed by diuretics / Na restriction • 6-8 g/of albumin per liter of ascites removed • Midodrine may be helpful – Shown to increase BP, survival benefit • Consideration of liver transplantation referral
- 44. Complications of Ascites • Hepatorenal syndrome – “The HRS Cocktail” • Albumin + Octreotide + Midodrine – In ICU: • Albumin + Norepineprhine • Hepatic Hydrothorax – NO CHEST TUBE!! – Same as acsites (Na restrict / diuretics)
- 45. Spontaneous Bacterial Peritonitis (SBP) Infectious complications of cirrhosis 1. Spontaneous bacterial peritonitis (SBP) 2. Urinary tract infection 3. Pneumonia 4. Bacteremia SBP 7-25% of hospitalized cirrhotics – In-hospital mortality 20-50% Recurrence of SBP 30-70% Borzio M Dig Liver Dis 2001;33(1):41-8 Runyon Hepatology 2004
- 46. Infecting Agents Eschericia coli 43% Klebsiella pneumoniae 8% Streptococcus pneumoniae 8% Alpha-hemolytic streptococcus 5% Group D stretocococcus 8% Miscellaneous Enterobacteriaceae 3% Miscellaneous 20% ASCITES
- 47. Spontaneous Bacterial Peritonitis (SBP) • Tap all patients admitted to hospital or for any reason rub you the wrong way… • Diagnosis: – Culture NOT needed (but send it anyways) – PMN >250cells/mm3 • Treatment: – 3rd gen cephalpsporin ie cefotaxime 2g q8 – Albumin 1.5g/kg day 1 and 1.0 g/kg day 3 • Cr >1, BUN >30, or bili >4
- 48. SBP : prevention • GI bleed and cirrhosis – Ceftriaxone or norflox x 7 days • If prior episode of SBP, long term prophylaxis – Daily norfloxacin or bactrim
- 50. Definition • Reversible alteration in the neuropsychiatric function • Due to shunting of neurotoxic nitrogenous products • Lack of hepatic detoxification
- 51. Hepatic Encephalopathy Pathogenesis Bacterial action Protein load Failure to metabolize NH3 NH3 Shunting GABA-BD receptors Toxins
- 52. 1 2 3 4 Coma Somnolence Confusion Drowsiness ?? ? ? ? ? Stages HE Adapted from AGA Teaching Slides.
- 53. Hepatic Encephalopathy (HE) • 10-50% of cirrhotics • 40% survival 1 year after 1st episode • 15% survival 3 years after 1st episode • Disturbance in diurnal sleep pattern precedes neurologic signs
- 54. Minimal Encephalopathy • 15-30% have abnormal NCT or abnormal EEG without overt encephalopathy • Significance unclear – impaired health-related quality of life (HRQOL) compared to patients with cirrhosis without minimal HE – impairs driving capacity and poor insight into their driving skills • Not replicated in real life conditions Metab Brain Dis 1998 Jun;13(2):159-72 Hepatology 1998 Jul;28(1):45-9 Metab Brain Dis 1995 Sep;10(3):239-48
- 55. Kappus et al Clinical Gastroenterology and Hepatology, Volume 10, Issue 11, 2012, 1208 - 1219 Classification of Hepatic Encephalopathy
- 56. Management of HE • Identify / treat precipitating factors • Empiric treatment – Rifaximin – Lactulose
- 57. GI bleedingExcess protein Sedatives / hypnotics TIPS Diuretics Serum K+ Plasma volume Azotemia Temp Infections Precipitating Factors of HE
- 58. Ammonia Levels in HE • May be correlation of ammonia levels and severity of HE • Diagnosis and treatment is clinical – Should not change management – No utility in following levels
- 59. Treatment of HE • Lactulose – First line – 2-3 soft BM/ day • Rifaximin – 550 BID – Reduced ammonia producing bacteria
- 60. Long Term Management of HE • After initial HE event – Usually on therapy indefinitely or until liver transplant – Long term use of lactulose and or rifaximin • High protein diet is OK (and preferred in cirrhosis) • Patients with HE should NOT undergo TIPS if possible
- 62. Pathophysiology • Occurs in setting of cirrhosis and ascites • Severe renal arterial vasoconstriction • Compromised glomerular filtration rate • Normal kidney structure
- 63. 1.0 0.8 0.6 0.4 0.2 0.0 Survival Type 1 hepatorenal syndrome Months Gines et al. NEJM 2004;350:1646-1654. P<0.001 Creatinine <1.2 mg/dL Creatinine 1.2-1.5mg/dL Creatinine >1.5mg/dL 1.0 0.8 0.4 0.2 0.0 1 2 3 4 5 Years Survival Refractory ascites Survival in Cirrhosis Based on Level of Renal Dysfunction Survival Among Patients With Cirrhosis and HRS 1 2 3 4 500 6 0.6 00 Survival is Decreased with Renal Dysfunction
- 64. Setting •Advanced liver disease: cirrhosis, alcoholic hepatitits, fulminant hepatitis •Sometimes precipitated by overdiuresis, GI bleed, use of nephrotoxic agents Clinical Features •Ascites • Oliguria •Hypotension • Jaundice Course •Typically death within weeks Hepatorenal Syndrome
- 65. Splanchnic/systemic vasodilatation Intrahepatic resistance Portal (sinusoidal) hypertension Activation of neurohumoral systems Cirrhosis Effective arterial blood volume Renal vasoconstriction HEPATORENAL SYNDROME
- 66. Type 1 and Type 2 HRS • HRS Type 1 – Rapidly progressive – Precipitating event frequent, esp SBP – Very short survival • HRS Type 2 – Slow onset of moderate renal insufficiency – Poor response to diuretics (refractory ascites) – Longer survival
- 67. 0 2 4 6 8 1210 Months 1 0.2 0.4 0.6 0.8 Survival probability 0 Type 2 p = 0.001 Gines et al., Lancet 2003; 362:1819 Type 1 Prognosis in Type 1 and 2 HRS
- 68. Precipitants of Type 1 HRS • Infection – Spontaneous bacterial peritonitis (SBP) – Urinary tract infection – Cellulitis • Gastrointestinal hemorrhage • NSAID use • Large volume paracentesis without albumin • Adrenal insufficiency
- 69. Salerno et al. Gut 2007 HRS Diagnostic Criteria 1. Cirrhosis with ascites 2. Serum CR >1.5 mg/dL 3. No improvement in serum CR after at least 2 days of diuretic withdrawal & volume expansion with albumin (max 100g/day) 4. Absence of shock 5. No current or recent nephrotoxic drugs 6. Absence of parenchymal kidney disease
- 70. Clinical Characteristics of HRS Ascites Advanced liver disease Low mean arterial pressure (median 74 mmHg) Low serum Na (median 127 mEq/L) Low urinary output Do not rely on urine Na or urine sediment to differentiate HRS from ATN Garcia-Tsao et al. Hepatology 2008
- 71. Prevention of AKI in cirrhotics Careful use of diuretics & lactulose Albumin after large volume paracentesis Avoid NSAIDs & aminoglycosides Albumin & antibiotics for treatment of SBP Primary prophylaxis of SBP with antibiotics Antibiotics for 5-7 days at time of GI bleed
- 72. Precipitants • Treatment principles • Treat the underlying precipitant promptly • More quickly addressed the more likely to have improvement in HRS • Have a high suspicion for an occult precipitating event in any liver patient who has ARF • Even with removal of the precipitant, HRS may be irreversible 72
- 73. Treatments • Precipitating events • Renal vasodilators • Systemic vasoconstrictors • TIPS • Dialysis • Transplantation 73
- 75. Hepatocellular Carcinoma • Seen in cirrhosis – Exception: HBV (can be noncirrhotic) • Diagnosis by US, CT scan, MRI – Histology is not essential • Alpha-fetal protein level may be elevated
- 76. Hepatocellular Carcinoma (HCC) • Surveillance – Screen all patients with cirrhosis for HCC • Up to 8% risk of HCC/year – Also male HBV carriers >40 and female HBV >50 (even if they don’t have cirrhosis) • Up to 0.6% risk of HCC/year • For boards…screen with ultrasound q 6 months – No benefit to shorten interval – No benefit to screen with AFP – In practice many still use cross sectional imaging and AFP to screen as well
- 77. Diagnosis of HCC • Usually with imaging, histology used less often • If lesion seen on u/s> 1cm then follow up with CT or MR – If hypervascular lesion that washes out on portal venous phase then dx with HCC – No bx needed
- 78. CT appearance of HCC Arterial Phase Arterial Phase Washout
- 79. Treatment of HCC • Resection • Local-Regional therapy – TACE – RFA – Ethanol ablation • Liver transpantation • Systemic – Sorafenib
- 80. Treatment of HCC • Resection – Less commonly used – Noncirrhotic or very well compensated • Well preserved synthetic function (INR near normal) • Normal bili • Low portal pressure – Possibly for noncirrhotic HBV patient.. – No role for adjuvant chemotherapy
- 81. Treatment of HCC • Local ablation – Alcohol injection • Only in smaller tumors • Not used very often – Radiofrequency ablation • Better for larger tumors – May use as a bridge to liver transplantation
- 82. Treatment of HCC • Transarterial Chemoebolization (TACE) – Non curative – Nonsurgical patients – Large multifocal HCC – No vascular invasion – No extrahepatic spread
- 83. Treatment of HCC • Liver transplantation – Curative approach – Milan Criteria • 1 tumor <5cm • Up to 3 tumors <3cm • No vascular / extrahepatic spread – Tumor exception points • MELD=22
- 84. Treatment of HCC • Sorafenib – Last resort – Cannot benefit from resection, transplantation, ablation or TACE – Multifocal disease with well preserved hepatic function – SHARP trial median survival 10.7 months vs 7.9 months average survival
- 85. Take Home: HCC • Screen patients with u/s q6 months if they have cirrhosis / older patients with HBV • Usually radiographic diagnosis – Biopsy rarely needed – Cross sectional imaging look for “arterial enhancement” and “washout” • Treatment: – Possibly “curative”: ablation, resection, transplant – Palliative: TACE, sorafenib
- 86. Prognostic Tools
- 87. Prognostic Models • Tools for predicting disease severity and death – Child-Turcotte-Pugh (CTP) score – Model or End-Stage Liver Disease (MELD)
- 88. Child-Pugh-Turcotte 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
- 89. MELD Score • Model for Endstage Liver Disease • MELD = INR, Creatinine, Bilirubin • Higher scores (6 to 40) indicate worse prognosis • MELD >15 would benefit from liver transplant
- 90. Conclusions • The transition from compensated cirrhosis to decompensated cirrhosis carries a significant change in mortality • Clinical diagnosis is important • Simultaneous compications may (and usually arise)
Editor's Notes
- Slide 204 CIRRHOSIS IS THE MOST COMMON CAUSE OF ASCITES Cirrhosis is the most common cause of ascites, accounting for 80% of cases. Peritoneal malignancy, heart failure and peritoneal tuberculosis are also common, accounting for another 15% of the cases. Less common causes of ascites include pancreatitis, hemodialysis and the Budd-Chiari syndrome. Of the most common causes, cirrhosis and heart failure are portal sinusoidal hypertensive causes of ascites, while peritoneal malignancy and tuberculosis are non-portal hypertensive causes. Runyon BA, In: Diseases of the Liver. Eds. Schiff L and Schiff ER,1993; Seventh Edition:990
- Slide 207 THE PERMEABILITY OF THE HEPATIC SINUSOID VARIES IN HEALTH AND DISEASE Unlike other capillaries, normal hepatic sinusoids lack a basement membrane. The sinusoidal endothelial cells themselves contain large fenestrae (200-400 nm in diameter), allowing passage of large molecules with molecular weight up to 250,000. These two features make the normal hepatic sinusoid very permeable with movement of fluid depending mostly on hydrostatic pressure. In cirrhosis, sinusoids become less permeable, as fibrous tissue is deposited in the space of Disse leading to the “capillarization” of the sinusoid, however these structures are still more permeable than splanchnic capillaries.
- Slide 350 PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY This slide demonstrates how ammonia bypasses the liver, either through porto-systemic collaterals or through a created shunt (transjugular intrahepatic porto-systemic shunt) and ultimately reaches the brain.