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A. Etiologynavigator

  1. Definitions
    1. Cirrhosis is hepatocellular regeneration with fibrosis
    2. Fibrosis describes encapsulation or replacement of injured tissue by collagenous scar
    3. Cirrhosis is advanced stage of liver fibrosis accompanied by distortion of hepatic vasculature
    4. Resultant vascular distortion leads to shunting of portal and arterial blood into hepatic outflow
  2. Major Causes of Cirrhosis in USA
    1. Prevalence >400,000 cases of cirrhosis (>0.15%) with >25,000 deaths in 1998
    2. Hepatitis C Virus (HCV) is the most common cause of new cases (>50%)
    3. Alcoholism is second leading cause of new cases; primary cause of older cases
    4. Chronic Hepatitis B Virus (HBV): 5-10% of cases
    5. Alcohol abuse increases risk of cirrhosis ~8 fold in hepatitis C virus infected patients [2]
  3. Intrahepatic
    1. Alcoholic liver disease
    2. Viral: chronic viral hepatitis (HBV, HCV, HDV)
    3. Non-alcoholic fatty liver (steatohepatitis, NASH) - most strongly associated with obesity [3]
    4. Drugs: nitrofurantoin, methyldopa, isoniazid, methotrexate, niacin, troglitazone
    5. Hemochromatosis [4,5]
    6. Biliary Cirrhosis: primary and secondary (obstructive)
    7. Sclerosing Cholangitis
    8. Sarcoidosis (rare)
    9. Wilson's Disease
    10. Porphyria Cutanea Tarda
    11. alpha1-antitrypsin deficiency
    12. Amyloidosis
    13. Metastatic disease
  4. Post-Hepatic
    1. Budd-Chiari Syndrome
    2. Right Heart Failure: "cardiac cirrhosis"
    3. Inferior Vena Cava Obstruction

B. Pathophysiology [1]navigator

  1. Cirrhosis
    1. Biopsy shows clusters of regenerating liver cells between bands of fibrotic tissue
    2. The fibrotic bands of connective tissue (collagen, others) prevent normal blood perfusion
    3. The parenchymal liver cells are generally functional
    4. Collagen is produced primarily by hepatic stellate cells (formerly called Ito cells or lipocytes)
    5. Portal myofibroblasts also have fibrogenic (collagen-producing) potential
    6. Collagen deposition is similar to chronic fibrotic wound healing response
    7. Result is high perfusion pressures through liver leading to portal hypertension
    8. Liver's ability to regenerate is high; the fibrotic nature of cirrhosis is main problem
    9. Uncommonly, the fibrotic tissue components may reverse with treatment
  2. Portal Hypertension
    1. Normally, hepatic sinusoids are lined by fenestrated endothelia
    2. These endothelia rest on a sheet of permeable connective tissue in the space of Disse
    3. Space of Disse also contains hepatic stellate cells and some mononuclear cells
    4. Other side of the space of Disse is normally lined by hepatocytes that carry out liver functions
    5. In cirrhosis, space of Disse filled with scar tissue causing loss of endothelial fenestrations
    6. This is called sinusoidal capillarisation: sinusoids become well-sealed capillaries
    7. The vascularised fibrotic septa that result are devoid of central vein
    8. This leads to elevations in pressures of vascular tree (portal hypertension)
    9. Portal hypertension causes ascites, varices, exacerbates hepatocyte dysfunction
  3. Ascites [6,22]
    1. Increased portal pressures (portal hypertension) forces exudation of vascular fluid
    2. Exudated vascular fluid collects in the peritoneal cavity forming ascites
    3. Exudation is exacerbated by reduced oncotic pressures due to hypoalbuminemia
  4. Varices
    1. Esophageal and Gastric
    2. Periumbilicular
    3. Perianal (hemorrhoids)
  5. Liver Synthetic Insufficiency
    1. Due to hypoperfusion of hepatocytes and increased portal pressures
    2. Coagulopathy
    3. Hypoalbuminemia - leading to edema
    4. Prothrombin time (PT), and not albumin level, is best predictor of hepatic function
  6. Vitamin Deficiency
    1. Reduced fat-soluble vitamin storage
    2. Vitamin K deficiency exacerbates coagulopathy
  7. Encephalopathy
    1. Believed to be due to accumulation of "toxins" normally metablized by liver
    2. Serum ammonia levels show moderate (r=0.5-0.6) correlation with severity of encephalopathy [8]
  8. Abnormal Peripheral Vasodilation [10]
    1. Believed to be related to increased bacterial endotoxin loads in cirrhotics
    2. Endotoxin stimulates nitric oxide production and vasodilation
    3. Nitric oxide implicated in renal dysfunction
    4. Antibiotics can reduce bacterial loads and reduce endogenous nitric oxide production
    5. Increased levels of aldosterone and angiotensin II
    6. These vasoconstrictors are likely counteracting elevated nitric oxide levels
    7. Levels of exhaled nitric oxide normalize after transplantation
    8. Elevated levels of atrial natriuretic peptide when patients are supine
    9. The increase in ANP due to pooling of excess fluid in right atrium when supine
  9. Hepatorenal Syndrome [6,10]
    1. Progressive renal failure with "pre-renal" insuffiency
    2. Believed to be due to hormonal actions on renal afferent arteriolar bed
    3. Nitric oxide overproduction appears to be a major contributor
    4. Nitric oxide leads to efferent arteriolar vasodilation, reduced GFR
    5. Also appears to stimulate marked sodium retention in distal tubules
    6. Vasodilation leads to compensatory increase in renin, angiotensin, aldosterone, antidiuretic hormone (ADH, vasopressin), and endothelin
    7. All of these agents act on the renal vasculature to cause afferent vasoconstriction
    8. Net renal perfusion pressure is greatly reduced
  10. Altered Drug Metabolism
    1. Increased half-lives for most drugs
    2. Reduced detoxification via P450 and other systems
  11. Portopulmonary Hypertension [11]
    1. Always in patients with portal HTN
    2. Pulmonary arterial pressure >25 mmHg + pulmonary vascular resistance > 240 dyn/s-cm
    3. Classified as pulmonary HTN associated with portal HTN or liver disease
    4. <5% of patients with cirrhosis have portopulmonary HTN
    5. Usually presents with progressive dyspnea on exertion
    6. Diagnosis with doppler echocardiography in most cases; right heart catheterization also
    7. Grade severity by NYHA class for heart failure
    8. Intravenous epoprostenol (Flolan®) is best studied agent in severe disease
    9. Bosentan (Tracleer®), an endothelin receptor blocker, may be used with caution
    10. Bosentan causes liver dysfunction in 15-20% of patients and careful monitoring required
    11. Ambrisentan (Letairis®), another endothelin receptor blocker, does not cause liver dysfunction
    12. Sildenafil (Revatio®), a phosphodiesterase V inhibitor, may also be used cautiously
    13. Presence of moderate to severe pulmonary HTN increases risk for liver transplantation
  12. Hepatopulmonary Syndrome [11,12]
    1. Due to increased arteriovenous shunting
    2. Likely due to nitric oxide overproduction from high bacterial (product) load in blood
    3. Levels of exhaled nitric oxide are >2X normal in patients with cirrhosis
    4. Patients have increased alveolar-arterial oxygen (A-a) gradients
    5. Pulmonary function tests usually show reduced carbon monoxide diffusion limit (DLCO)
    6. Liver transplantation normalizes nitric oxide levels as well as A-a gradients

C. Symptoms
[Figure] "The Biliary Tract" navigator

  1. Jaundice (bilirubin >4mg/dL usually required for appearance of jaundice)
  2. Coagulopathy
    1. Purpura and bleeding due to clotting factor deficiencies
    2. Thrombocytopenia often present as well (mainly due to splenomegaly)
  3. Portal Hypertension [6]
    1. Ascites
    2. Varices
    3. Peripheral edema
    4. Vascular (mainly venous) dilatation
  4. Abnormal Venous Dilatation
    1. Spider angiomata - central arteriole with tiny radiating vessels, mainly trunk and face
    2. Caput medusae - prominent veins radiating from umbilicus
    3. Palmar erythema - erythema sparing central portion of palm
  5. Impaired wound healing
  6. Hypertrophic osteoarthropathy / finger clubbing - painful proliferative lesions of long bones
  7. Elevated Estrogen Effects
    1. Reduced degradation of estradiol in liver; enhanced estradiol production
    2. Contribute to spider angiomata, palmar erythema
    3. Gynecomastia
    4. Loss of male hair pattern
  8. Increased risk of developing hepatocellular carcinoma (HCC)
    1. Particularly increased in patients with chronic hepatitis B and/or C virus infections
    2. Interferon alpha reduces risk of HCC in HBV or HCV infected patients [7]
  9. Encephalopathy (see above)
  10. Progression
    1. Decompensation rates annually are 4% for HCV and 10% for HBV infected patients
    2. HCC risk (without treatment) are 2-7% per annum

D. Laboratory navigator

  1. Electrolytes (hyponatremia, hyperkalemia, acidosis)
  2. Renal function (hepatorenal syndrome)
  3. Complete Blood Count (elevated infection risk; bacterial peritonitis)
  4. Liver Function Tests
    1. Parenchymal Cells: transaminases AST (SGOT), ALT (SGPT)
    2. Bile Duct Cells: alkaline phosphatase, gamma-glutamyltransferase (GGT), 5'-nucleotidase
    3. Bilirubin and Direct (Conjugated) Bilirubin
    4. Synthetic Function: albumin, prothrombin time (vitamin K dependent)
  5. Ultrasonography is generally recommended
    1. Nodularity and increased echogenicity of liver in cirrhosis (also in steatosis)
    2. Atrophy of the right lobe and hypertrophy of the left and caudate lobes
    3. Evaluation of portal vein blood flow - portal hypertension and patency
    4. Evaluation of possible hepatocellular carcinoma or other liver masses
  6. HCC Screen: alpha-fetoprotein level
  7. Helical CT or MRI with contrast preferred if HCC or vascular lesions suspected

E. Liver Biopsy [13] navigator

  1. Gold standard for diagnosis of cirrhosis
  2. Diagnosing, grading and/or staging of chronic hepatitis
    1. Alcoholic liver disease
    2. Steatohepatitis
    3. Autoimmune hepatitis
  3. Several methods are used for obtaining liver tissue
    1. Percutaneous
    2. Transjugular
    3. Laparoscopic
    4. Fine needle (guided by ultrasound or computed tomography)
  4. Size of biopsy typically 1-3cm in length and 1.2-2mm in diameter
  5. For diffuse liver disease, at least 1.5cm length of tissue is required
  6. Most common complication is bleeding from biopsy site
  7. Biochemical markers of fibrosis may be used to avoid biopsy in some patients with HCV infection [21]

F. Therapeutic Overview [1]navigator

  1. Monitoring and correcting complications is critical
  2. Vitamin Replacement
    1. Particularly fat-soluble vitamins
    2. Vitamin D
    3. Vitamin E
    4. Vitamin K
  3. Ursodeoxycholic acid (Actigal®) to reduce pruritus, may improve pathology
  4. Ascites Treatment (see below)
    1. Fluid restriction
    2. No-salt added diet
    3. Spironolactone or eplerenone usually first line
    4. Furosemide or other loop diuretic often needed
    5. Paracentesis may be required
    6. Monitor for spontaneous bacterial peritonitis
  5. Portal Hypertension Reduction (see below)
    1. Nonselective ß-blockers: propranolol, naldolol
    2. Nitrates
    3. Invasive procedures
  6. Encephalopathy
    1. Lactulose usually first line
    2. Bowel bacteria reduction (neomycin or other agent) may help
    3. Benzodiazepine receptor antagonists can temporarily reverse some symptoms
    4. Glucocorticoids may be of some benefit
  7. Glucocorticoids
    1. Improve mortality in some patients with alcoholic cirrhosis
    2. Patients with encephalopathy benefit from prednisone (20-60mg/d; taper over 3-4 wks)
    3. Patients with "Descriminant Function" > 32 benefit with prednisolone 20mg/d
    4. Descriminant Function = 4.6x(PT-Control)+Bilirubin
    5. This function is an attempt to quantitate level of hepatic dysfunction
    6. Except in these specific patients, routine use of glucocorticoids in not recommended
  8. Vaccinations
    1. Hepatitis A and B vaccines
    2. Pneumococcus
    3. Influenza
  9. Evaluation for liver transplantation

G. Treatment of Ascites [6] navigator

  1. Diuresis (~85% response)
    1. Spironolactone - dose up to 600mg daily divided; initiate 25mg po qd
    2. Furosemide - dose up to 160mg daily divided; initiate 20mg po qd in edematous patients
    3. Complications (depletion of intravascular volume): hyponatremia, renal insufficiency
    4. Now considered 2nd line therapy for ascites (after Paracentesis with Albumin)
  2. Large Volume Paracentesis [22]
    1. Very effective in reducing volume load and discomfort (~100% response)
    2. Volumes removed: 4-6 liters / day
    3. Requires albumin infusions to prevent intravascular depletion (~12.5gm / 2L removed)
    4. Hospital stay decreased compared with diuretic therapy
    5. Paracentesis with albumin infusions is now considered primary treatment
  3. Albumin Infusions
    1. Intravascular volume increase
    2. Replenish albumin in protein-deficient host
    3. Renal failure / hyponatremia decreased in patients following large volume paracentesis
    4. In patients with cirrhosis and spontaneous bacterial peritonitis, albumin infusions reduced risk of renal failure and death by 40-70% [14]
  4. Paracentesis (with IV albumin infusion) compared to Peritoneovenous shunting [15]
    1. Shown to be equally effective early in treatment of recurrent ascites
    2. However, incidence of recurrent ascites within 3 months of proceedure was 82% in the paracentesis versus 39% in the shunt group [15]
    3. Overall incidence of complications is similar
    4. Patients undergoing paracentesis required more use of diuretics at follow up
    5. Readmissions rates for all causes (including ascites) higher in paracentesis patients
    6. Compared with large volume paracentesis, portosystemic shunts reduces risk of progression to liver transplant over 48 months [15]
    7. Therefore, portosystemic shunts are preferred for long term management of ascites
  5. Refractory ascites may respond to TIPS procedure (see below)
  6. Nitric oxide synthesis blockers improve renal function and diuresis in animal models [10]
  7. Selective intestinal decontamination with norfloxacin 400mg po bid x 4 weeks partially reverses hyperdynamic circulatory state in cirrhosis without harming kidney [17]

H. Treatment of Varices navigator

  1. Overview
    1. Patients with esophageal varices have high portal pressures
    2. Varices develop in response to the increased "liver-bypass" blood flow
    3. Varices are dilated veins which are quite superficial and bleed easily
    4. Issues include: prevention of first bleed, treating acute bleeding, and preventing rebleed
    5. In general, reduction of portal pressures reduces risk of bleeding
    6. Variceal bleeding is a medical emergency with a high mortality risk
  2. Decrease Portal Pressures
    1. Non-selective ß-blockers propranolol and nadolol prolong time to first variceal bleed
    2. They have less of an effect on time until second (re-) bleed
    3. ß-blockers do not prevent development of varices in cirrhotic patients with portal HTN [18]
    4. ß-Blocker dose should be increased until heart rate decreases by ~25%
    5. Isosorbide mononitrate 20mg tid is as effective as propranolol at prevention of rebleed
    6. Goal is >20% reduction in portal pressures, which significantly reduces rebleed risk
  3. Sclerotherapy
    1. Initial bleed prophylaxis with sclerotherapy increases mortality
    2. Endoscopic ligation is preferable to sclerotherapy for therapy of bleeding varices
    3. Ligation should be combined with octreotide (or vasopressin) for 48 hours
    4. Sclerotherapy has shown mortality benefit in patients who have had a first bleed
    5. Over long term, sclerotherapy showed low rebleeding rates
    6. Most patients (70%) required repeat sclerotherapy within one year of initial therapy
  4. Acute Variceal Bleeding
    1. Goal is reduction of portal pressures and variceal vasoconstriction
    2. This is a medical/surgical emergency with high mortality potential
    3. Vasopressin was originally the mainstay of therapy, causing vasoconstriction
    4. Nitroglycerin iv is often given along with vasopressin to prevent cardiac ischemia
    5. Octreotide (Sandostatin®) IV + sclerotherapy superior to sclerotherapy alone at controlling bleeding, but no improvement in short term mortality
    6. In a meta-analysis, octreotide IV did not increase survival or reduce blood transfusion [19]
    7. However, octreotide reduces rebleeding by ~90% combined with variceal ligation [20]
    8. Surgical correction of bleeding varices may be required in refractory cases
    9. Systemic antibiotics should be given to reduce the risk infection during bleeding
  5. Combined endoscopic and drug therapy prevents rebleeding of varices better than either therapy alone with a trend to mortality benefit [9]
  6. Short Term Mortality: Surgery versus Sclerosis
    1. Mortality elevated in surgically therapy versus sclerosed patients with first variceal bleed
    2. These were Child Grade A and B (mild and moderate) varices
    3. Rebleeding slightly higher in sclerosed patients though not generally significant
    4. In-hospital morbidity much higher with surgical patients
  7. Transjugular Intrahepatic Portosystemic Stent-Shunt (TIPS)
    1. Treatment for portal hypertension and ascites and recurrent variceal bleeding
    2. Conduit from portal vein to hepatic vein (IVC) placed transvenously
    3. Internal jugular vein entered and catheter advanced through IVC into R hepatic vein
    4. Intraheptic branch of portal vein is punctured seperately to establish a shunt
    5. Stent is placed (tubular wire mesh) to form shunt tract
    6. High success rates generally reported (90-100%) for placement
    7. Safe and effective therapy for variceal bleeding by reducing portal pressure
  8. Surgical Shunt Procedures
    1. These procedures provide shunt between mesenteric (portal) and systemic circulation
    2. Bypass liver, lower portal hypertension, ascites formation, esophageal bleeding
    3. The degree of hepatic encephalopathy is nearly always increased

I. Treatment of Coagulopathy navigator

  1. Prothrombin time best predictor of hepatic synthetic function
  2. Deficiencies in Vitamin K - correct with 10mg sc qd x 3 doses
  3. Platelets
  4. Fresh-Frozen Plasma
  5. Cryoprecipitate (for low fibrinogen if DIC-like syndrome)

J. Treatment of Encephalopathy navigator

  1. Low protein Diet
  2. Lactulose: increase colonic pH to reduce absorbtion of ammonia (? and other toxins)
  3. Neomycin / Metronidazole or Norfloxacin [17] oral: reduce colonic bacteria
  4. Monitor by blood (arterial) ammonia levels
  5. Corticosteroids improve cirrhotic encephalopathy
  6. Surgical (and TIPS) Shunt procedures increase incidence of encephalopathy

K. Evaluation of Liver Transplant navigator

  1. Focus on operative risks and mortality; assessed with Child's or MELD criteria [1]
  2. Child's Criteria
    1. Bilirubin Level
    2. Albumin
    3. Ascites
    4. Encephalopathy
    5. Nutritional Status
    6. Obesity (technical difficulty)
  3. MELD (Model for End Stage Liver Disease) best predicts 3-month mortality in cirrhotics regardless of cause (focus on creatinine, bilirubin, and INR/prothrombin time)

References navigator

  1. Schuppan D and Afdhal NH. 2008. Lancet. 371(9615):838 abstract
  2. Harris DR, Gonin R, Alter HJ, et al. 2001. Ann Intern Med. 134(2):120 abstract
  3. Clark JM and Diehl AM. 2003. JAMA. 289(22):3000 abstract
  4. Tulloch L, Ruskin NJ, Creamer J. 2007. Lancet. 370(9591):1006 abstract
  5. Morrison ED, Brandhagen DJ, Phatak P, et al. 2003. Ann Intern Med. 138(8):627 abstract
  6. Gines P, Cardenas A, Arroyo V, Rodes J. 2004. NEJM. 350(16):1646 abstract
  7. Baffis V, Shrier I, Sherker AH, Szilagyi A. 1999. Ann Intern Med. 131(9):696 abstract
  8. Ong JP, Aggarwal A, Krieger D, et al. 2003. Am J Med. 114(3):188 abstract
  9. Gonzalez R, Zamora J, Gomez-Camarero J, et al. 2008. Ann Intern Med. 149(2):109 abstract
  10. Martin PY, Gines P, Schrier RW. 1998. NEJM. 339(8):533 abstract
  11. Hoeper MM, Krowka MJ, Strassburg CP. 2004. Lancet. 363(9419):1461 abstract
  12. Rolla G, Brussino L, Colagrande P, et al. 1998. Ann Intern Med. 129(5):375 abstract
  13. Bravo AA, Sheth SG, Chopra S. 2001. NEJM. 344(6):495
  14. Sort P, Navasa M, Arroyo V, et al. 1999. NEJM. 341(6):403 abstract
  15. Rossle M, Ochs A, Gulberg V, et al. 2000. NEJM. 342(23);1701 abstract
  16. Christensen E and Gluud C. 1995. Gut. 37:113 abstract
  17. Rasaratnam B, Kaye D, Jennings G, et al. 2003. Ann Intern Med. 139(3):186 abstract
  18. Groszmann RJ, Garcia-Tsao G, Bosch J, et al. 2005. NEJM. 353(21):2254 abstract
  19. Gotzshce PC, Fjorup I, Bonnein H, et al. 1995. Brit Med J. 310:1495 abstract
  20. Sung JJ, Cuhng SC, Yung MY, et al. 1995. Lancet. 346:1666 abstract
  21. Imbert-Bismut F, Ratziu V, Pieroni L, et al. 2001. Lancet. 344(9262):1069
  22. Wong CL, Holroyd-Leduc J, Thorpe KE, Straus SE. 2008. JAMA. 299(10):1166 abstract