Hepatitis and cirrhosis

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1.   HEPATITIS AND CIRRHOSIS SAMIR EL ANSARY

2. Hepatitis is defined as inflammation of the liver. It can be divided into infectious and noninfectious causes.

3. Liver function tests The term liver function tests (LFTs) commonly refers to Alkaline amino- transferase (ALT), A spartate aminotransferase (AST), A lkaline phosphatase Bilirubin , albumin, and protein.

4. Liver function tests ALT and AST ( transaminases ) are enzymes found in hepatocytes whereas alkaline phosphatase is found in cells in the bile ducts.

5. Gamma- glutamyl transpeptidase is an additional test that is used to determine whether Alkaline phosphatase elevations originate from hepatobiliary sources. Prothrombin time is used to assess liver synthetic function.

6. Elevations of which LFTs are associated with hepatitis Hepatitis is a process of hepatocellular inflammation and damage that causes spillage of cellular elements into the blood. Hepatitis therefore results primarily in elevations in ALT and AST. Elevations can be modest in some forms of hepatitis (alcoholic) or extreme in others (acute viral hepatitis).

7. Alkaline phosphatase Levels can also be elevated in hepatitis, but elevations are generally less significant than those of the transaminases . Bilirubin Can reach very high levels in hepatitis but usually lags behind the transaminases .

8. Types of infectious hepatitis Hepatitis viruses primarily infect the liver and include hepatitis A, B, C, D, and E. Other nonhepatitis viruses can cause hepatitis including C ytomegalovirus, Epstein-Barr virus, and human immunodeficiency virus (HIV).

9. Hepatitis A, how is it diagnosed, and what are the disease course and management? Hepatitis A is a disease caused by an RNA virus that is transmitted by the fecal-oral route, is endemic in the developing world, and occurs sporadically in the United States. Most childhood infections are asymptomatic. Adults are more likely to have acute symptoms.

10. The incubation period is 2 to 6 weeks, after which patients have fatigue, malaise, fever, and abdominal pain followed by jaundice. Transaminase levels are markedly elevated. Diagnosis is by a positive anti-hepatitis A virus (HAV) immunoglobulin ( lg ) M antibody that denotes active infection and remains elevated for 3 to 6 months. HAV anti- lgG antibody positivity occurs later, remains elevated for decades, and indicates past infection.

11. Treatment is supportive. Significant morbidity and mortality are uncommon, but development of fulminant hepatic failure (FHF) can occur (<I%) and carries significant mortality . HAV vaccine is effective and widely available. It is recommended for individuals with chronic liver disease, child-care workers, and those traveling to endemic areas.

12. Hepatitis E Like HAV, hepatitis E virus (HEV) is an RNA virus that is transmitted by the fecal-oral route. It is endemic to Southeast Asia, Africa, India, and Central America. Infection in the United States is uncommon and is almost always associated with individuals who have recently traveled to endemic areas.

13. It causes a self-limiting hepatitis similar to HAV infection but has a significantly higher tendency to progress to FHF in pregnant women. Laboratory tests for diagnosis include HEV IgG and IgM antibody testing As well as HEV RNA polymerase chain reaction (PCR).

14. Hepatitis B

15. Hepatitis B is a disease caused by A DNA virus that is transmitted through blood and body fluids. Risk factors include intravenous (IV) and intranasal drug use, unprotected sex with multiple partners, men who have sex with men, health care workers exposed to blood, children born to infected mothers, incarceration, and spouses of infected individuals.

16. Acute infection Is most commonly asymptomatic but can cause constitutional symptoms including fatigue, malaise, nausea, vomiting, headache, arthralgias , myalgias , and low-grade fever, as well as jaundice, dark urine, clay-colored stools, and tender hepatomegaly .

17. FHF occurs in 1% of infections . Other complications include a serum sickness-like syndrome (5%-10% of cases), glomerular nephritis with nephrotic syndrome , systemic vasculitis And progression to chronic hepatitis B infection which occurs in approximately 5% of cases.

18. Some individuals go on to a carrier state in which they have persistent hepatitis B virus (HBV) in the liver without any significant inflammation. These individuals can be infectious and are termed I nactive carriers.

19. How is hepatitis B diagnosed

20. Serologic testing for hepatitis B is complicated by the fact that there are multiple blood tests routinely used to assess infection.

21. Hepatitis B surface antigen ( HBsAg ) Is the lipid and protein layer that forms the outer shell of HBV. It is not infectious and is produced in excess during viral replication. It is the first viral antigen to become positive in the serum with acute infection, and its presence indicates active infection. It may be negative early in the acute infection And it is also the first serum marker to be cleared by the host immune system Becoming undetectable 6 to 12 weeks after infection.

22. Hepatitis B surface antibody ( HBsAb ) Is the antibody to HBsAg . It develops to detectible levels 6 to 8 weeks after infection and remains detectible for life. Positive HBsAb indicates past or resolving infection. Hepatitis B vaccine uses the surface particle, and vaccinated individuals will also be HBsAb positive.

23. Hepatitis B core antibody ( HBcAb ) is an antibody to a core viral protein. HBcAb can be measured as IgG or lgM and can also be reported as total, which includes both. lgM makes up the immune system's early response and is later replaced by IgG . Positive HBcAb lgM indicates early or acute infection. Positive HBcAb IgG indicates past or chronic infection.

24. Hepatitis B early antigen ( HBeAg ) Is a protein produced during viral replication And detectible levels of this antigen indicate high levels of viral replication I ncreased infectivity And higher risk of progression to fibrosis. It is positive during both acute infection and active viral phases of chronic infection.

25. HBV DNA Can also be measured and is one of the diagnostic criteria For Chronic HBV infection.

26. Hepatitis C

27. Hepatitis C is caused by a blood-borne RNA virus. It is transmitted primarily through contact with blood products from infected individuals. Risk factors include current or past IV drug use, health care workers exposed to blood Or transfusion of infected blood products (rare since routine screening was introduced in 1992).

28. Sexual transmission can occur but is uncommon with hepatitis C virus (HCV). Most acute infections are asymptomatic But 20% to 30% of infected individuals will have A self-limiting illness similar to other acute viral hepatitis infections.

29. A majority (70%-85%) of those infected with HCV will go on to have chronic infection. It is currently estimated that more than 3 million individuals have chronic HCV in the United States, where it is the leading indication for liver transplantation.

30. How is HCV infection diagnosed? Screening for infection is by serum testing for anti-HCV antibody. Antibody positivity occurs at 4 to 10 weeks and remains positive for life regardless of whether Chronic infection develops.

31. All positive antibody tests should be followed up with an HCV RNA PCR to determine whether active infection exists. Of those infected, 15% to 25% will spontaneously clear the virus and are not at risk for complications of chronic infection. If virus is detected Viral genotyping should be done.

32. HCV genotypes And how do they affect management? At least six genotypes and more than 50 subtypes of HCV have been identified. Genotype 1 is the most common genotype, accounting for 60% to 80% of all hepatitis C. Genotype 1 is more difficult to eradicate with treatment than other common genotypes.

33. Treatment for chronic hepatitis C infection is with pegylated interferon-a and ribavirin . Treatment length is dependent on genotype and viral response. Genotype 1 traditionally requires a longer treatment course (48 weeks) and has lower response rates (50%).

34. Recent data have shown that the addition of Telaprevir or Boceprevir to interferon and ribavirin for treatment of genotype 1 hepatitis C infection significantly improves achievement of sustained viral response to levels similar to those of other common hepatitis C genotypes.

35. Other extrahepatic conditions can be caused by Hepatitis C infection Some individuals with chronic hepatitis C infection can have other medical conditions that are thought to be due to the body's immune response to the HCV infection. These conditions are uncommon They include diabetes mellitus, glomerulonephritis , mixed cryoglobulinemia , porphyria cutanea tarda , and non-Hodgkin lymphoma.

36. Hepatitis D Hepatitis D virus (HDV) or hepatitis delta virus is a small RNA viral particle that can cause infection only in the presence of hepatitis B virus. It is blood borne, and IV drug use is the most common route of infection. Infection can occur either as coinfection when both HBV and HDV viruses are acquired together or as superinfection when HDV infection occurs in a patient with chronic hepatitis B infection.

37. Hepatitis D Concomitant infection with hepatitis B and D results in a higher likelihood of development of FHF More rapid progression to cirrhosis, and higher rates of hepatocellular carcinoma.

38. Viral serologies should be tested in a patient with acute hepatitis All patients with Acute hepatitis should undergo testing for Anti-HAV IgM , anti-HCV antibody, HBsAg , and HBcAb .

39. Who should be screened for HCV infection? Because chronic hepatitis C infection is prevalent and treatment can reduce the morbidity and mortality associated with infection, screening is recommended for anyone who has used injection drugs, people who received clotting factors before 1987 or other blood products before 1992 , patients undergoing hemodialysis , those with unexplained abnormal LFTs, health care

40. Workers with needle-stick injuries, individuals positive for HIV, and babies born to women positive for HCV. Patients with similar risk factors should be screened for HBV as well.

41. Risks associated with chronic hepatitis Chronic hepatitis can develop with HBV, HCV, and HDV infections, as well as many nonviral causes of hepatitis. It is characterized by persistent liver inflammation. Chronic hepatitis is associated with the development of liver fibrosis and cirrhosis and with increased risk for the development of hepatocellular carcinoma .

42. Nonviral causes of hepatitis There are many nonviral causes of hepatitis, which can be broken down into several broad categories including Toxic or drug induced, autoimmune, and metabolic. The list of drugs and toxins that can cause liver injury is extensive. The two most common causes of drug- or toxin induced liver injury are Alcohol and acetaminophen.

43. Nonviral causes of hepatitis Metabolic causes of hepatitis include hemochromatosis , Wilson disease, and nonalcoholic fatty liver disease. Hepatitis can also develop as a result of other organ system dysfunction. An example of this is liver hypoperfusion in shock states, known as S hock liver.

44. A utoimmune hepatitis (AIH) AIH is a chronic inflammatory liver disease caused by a host immune response to portions of the hepatocyte . This chronic inflammation can lead to progressive fibrosis and cirrhosis if left untreated. AIH can occur at any age but occurs most often in young women and is commonly associated with other autoimmune disorders.

45. Circulating autoantibodies associated with AIH are antinuclear antibody, anti-smooth muscle antibody, and liver kidney microsomal antibody. Elevated immunoglobulin levels are also common. Liver biopsy is necessary for diagnosis of AlH . Treatment is with steroids alone or in combination with azathioprine , and remission can be achieved in 60% to 80% of cases.

46. How is alcoholic hepatitis managed Alcoholic hepatitis can have a 1-month mortality rate as high as 30% to 50%. The Maddrey discriminant function score is a validated mechanism to score disease severity. It uses Prothrombin time and total bilirubin T o calculate a disease severity score with scores >32 indicating severe disease.

47. How is alcoholic hepatitis managed Data suggest that patients with severe disease benefit from treatment with a 4-week course of steroids or pentoxifylline if steroids are contraindicated. Additionally all patients with alcoholic hepatitis should be counseled to abstain from alcohol and should undergo nutritional assessment and Receive aggressive nutritional therapy.

48. FULMINANT HEPATIC FAILURE {FHF} FHF or acute liver failure is a gastrointestinal emergency characterized by the rapid arrest of normal hepatic function. A defining feature of FHF is the rapid onset of hepatic encephalopathy. FHF can result from the most severe forms of most of the causes of hepatitis. This includes the viral hepatitides , drugs, toxins, autoimmune hepatitis, and metabolic conditions affecting the liver.

49. In addition to encephalopathy, FHF can result in coagulopathy , increased risk for infection , metabolic derangements including acute renal failure, electrolyte abnormalities, hypoglycemia And pancreatitis.

50. Significant cardiorespiratory and hemodynamic sequelae of FHF also occur that are characterized by Hypotension resulting from low systemic vascular resistance, increased cardiac output, and tissue hypoxia.

51. Treatment and prognosis of FHF Treatment for patients with FHF is supportive while allowing the liver time to regenerate. Mortality rates are high, and the only intervention with proved benefit is Liver transplantation . Early referral to a transplant center should be considered when FHF is suspected.

52. Some causes of FHF can be reversed with immediate treatment and should be assessed for rapidly. These include acetaminophen, amanita mushroom poisoning, herpes simplex virus, acute fatty liver disease of pregnancy, and Wilson disease.

53. What is cirrhosis? Cirrhosis is a progressive process of hepatic injury, subsequent fibrosis, and destruction of normal liver architecture. It may result from any chronic liver disease but is most commonly associated with viral hepatitis and alcoholic liver disease.

54. What are the causes of cirrhosis? The most common causes of cirrhosis are Alcoholic liver disease and hepatitis C. Cryptogenic cirrhosis accounts for up to 18% of cases. Many cryptogenic cases may be due to nonalcoholic fatty liver disease.

55. Other causes include hepatitis B, autoimmune hepatobiliary disease , hemochromatosis , extra-hepatic biliary obstruction, Wilson disease a,-antitrypsin deficiency and drug toxicity.

56. Clinical presentation of cirrhosis Cirrhosis is often asymptomatic and discovered incidentally. Well-compensated cirrhosis Can manifest as anorexia and weight loss weakness, and fatigue.

57. More progressive disease may present with the following signs: jaundice, pruritus , coagulopathy , increasing abdominal girth, splenomegaly , abdominal wall vascular collaterals (caput medusae ), spider telangiectasia , palmar erythema , mental status changes, and asterixis . Advanced cirrhosis may present with severe complications such as upper gastrointestinal tract bleeding or hepatic encephalopathy.

58. How is cirrhosis diagnosed? Liver biopsy provides the definitive diagnosis of cirrhosis and may be indicated when the clinical diagnosis is uncertain. Abdominal ultrasound findings of liver nodularity , irregularity, increased echogenicity , and atrophy are consistent with cirrhosis. LFTs (including prothrombin time and albumin), hepatitis serologies , autoantibodies , and a complete blood cell count may reveal the underlying causes of cirrhosis and the extent of liver dysfunction.

59. Major complications of cirrhosis The most common complication of cirrhosis is ascites , followed by gastroesophageal variceal hemorrhage and hepatic encephalopathy . Ascites and variceal hemorrhage are direct consequences of portal hypertension.

60. Portal hypertension Portal hypertension is defined as a portal pressure of Greater than 12 mm Hg or a hepatic venous wedge pressure that exceeds the pressure of The inferior vena cava by > 5 mm Hg

61. The portal hypertension of cirrhosis is caused by The disruption of hepatic sinusoids leading to increased resistance in the portal venous system.

62. A compounding effect is increased portal flow due to vasodilation and increased cardiac output associated with cirrhosis. This leads to an imbalance of Starling forces , which results in fluid accumulation in the peritoneal cavity ( ascites ), as well as gastroesophageal varices .

63. O ther complications of cirrhosis Altered hemodynamics , hyponatremia immune compromise and Coagulopathy .

64. How is cirrhotic ascites diagnosed? New-onset ascites should be assessed with Diagnostic paracentesis to confirm cirrhosis as the cause and rule out Spontaneous bacterial peritonitis (SBP).

65. The Serum/ ascites albumin gradient (SAAG) is the most important diagnostic parameter in determining the cause of ascites . A SAAG of > 1.1 g/ dL indicates ascites from portal hypertension with a specificity of 97%. Ascitic fluid cell count, differential, and total protein should also be performed . Ascitic fluid culture should be obtained if any suspicion of SBP exists.

66. How is cirrhotic ascites managed? Initial management focuses on dietary sodium restriction and abstinence from alcohol in alcohol related liver disease. Diuretic therapy is the mainstay of medical management of ascites . Dual therapy with furosemide and spironolactone is the recommended starting regimen if renal function is stable.

67. Large-volume paracentesis is used to relieve the discomfort of tense ascites . Serial paracentesis may be indicated for ascites refractory to medical therapy. Transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation should be considered in refractory cases. Surgically placed peritoneovenous shunts may be an option in patients who are not candidates for paracentesis , TIPS, or transplantation .

68. Large-volume paracentesis is used to relieve the discomfort of tense ascites . Serial paracentesis May be indicated for ascites refractory to medical therapy. Transjugular intrahepatic portosystemic shunt (TIPS ) and liver transplantation should be considered in refractory cases.

69. TIPS TIPS is a treatment for portal hypertension. It is reserved for patients with severe A scites and variceal bleeding who do not respond to medical therapy. Reduced portal pressure is achieved by a stent placed through the liver between the portal and hepatic circulation.

70. Complications of cirrhotic ascites Ascites is associated with the complications of SPONTANEOUS BACTERIAL PERITONITIS {SBP} And the Hepatorenal syndrome (HRS). Mortality of cirrhotic ascites Cirrhotic ascites carries a 3-year mortality rate of 50%.

71. How is SBP diagnosed and managed? A positive ascitic fluid culture and absolute polymorphonuclear leukocyte (PMN) count of > 250 cells/mm3 Are diagnostic of SBP in the absence of an intraabdominal , surgically treatable source of infection.

72. Empirical antibiotics should be initiated for SBP in any hospitalized patient with an ascetic fluid PMN count of >250 cells/mm3 or an ascitic protein level of less than 1 g/ dL or in a patient with clinical suspicion of SBP (i.e., fever, abdominal pain) regardless of PMN count.

73. A third generation cephalosporin is the initial antibiotic choice, ideally C efotaxime . Oral ofloxacin is an acceptable substitute in patients who are quinolone naive and are clinically stable.

74. Risk factors for SBP, and how is it prevented Risk factors for SBP include prior SBP, variceal hemorrhage, and low-protein ascites . Prevention of SBP may be achieved with use of Quinolones or a third-generation cephalosporin in patients with variceal hemorrhage.

75. Oral quinolones may be used in patients who have had prior episodes of SBP. Antibiotic prophylaxis may be considered in those with low-protein ascites .

76. HEPATO RENAL SYNDROME HRS and how is it managed HRS is renal dysfunction ( creatinine level >1.5 mg/Dl) that persists after 2 days of diuretic withdrawal and volume expansion in patients with cirrhosis and ascites .

77. Type I HRS is rapidly progressive and fatal without treatment. Type II HRS progresses over months with a median survival of 3 to 6 months. Type I HRS warrants an expedited referral for liver transplantation. Dialysis may be needed to bridge patients to transplantation. Medical therapies such as O ctreotide and Midodrine may be used as temporizing measures as well.

78. Variceal bleeding Variceal bleeding is upper gastrointestinal tract bleeding due to rupture of gastroesophageal varices . It is the most common life-threatening complication of cirrhosis and occurs at a rate of 5% to 15% per year in patients with cirrhosis. Size of varices and severity of liver disease are the most important predictors of bleeding.

79. How is variceal bleeding prevented? At the time cirrhosis is diagnosed, esophago-gastroduodenoscopy (EGD) should be performed to screen for varices . If medium to large varices are present with a high risk of bleeding Nonselective p-blocker therapy or Endoscopic variceal ligation (EVL) is recommended.

80. For medium varices or small varices with a high risk of bleeding Non-selective p-blocker therapy is preferred with Endoscopic variceal ligation EVL reserved for patients intolerant to p-blocker therapy.

81. Other sources of upper gastrointestinal tract bleeding in patients with cirrhosis Sources include portal hypertensive gastropathy and gastric antral vascular ectasia .

82. How is variceal bleeding managed? Acute management consists of volume resuscitation , blood transfusion to maintain a hemoglobin level of > 8 g/Dl and EGD within 12 hours to diagnose variceal bleeding and treat with E ndoscopic variceal ligation EVL or sclerotherapy .

83. Medications that promote Splanchnic vasoconstriction are also used ( O ctreotide , a somatostatin analog And terlipressin ).

84. Balloon tamponade Is an effective short-term strategy to control bleeding, but it carries a 20% mortality rate due to complications. TIPS.

85. Short-term antibiotic treatment Is indicated in patients with Variceal bleeding and ascites Because of their high risk for SBP, other infections, and subsequent risk of rebleeding .

86. A 7-day course of N orfloxacin (400 mg twice daily) is recommended. IV ciprofloxacin May be used in patients unable to tolerate the oral route. Ceftriaxone Is an alternative in areas with high quinolone resistance.

87. Hepatic encephalopathy Hepatic encephalopathy is a syndrome of altered mental status in the setting of Portosystemic shunting Either through Collateral vessels or through surgically placed shunts.

88. Hepatic encephalopathy The mechanism is uncertain but may relate to changes in the blood-brain barrier that allow passage of neurotoxic substances, including ammonia and manganese , into the brain. Another theory suggests that accumulation of circulating ammonia due to Decreased hepatocyte function leads to encephalopathy .

89. How is hepatic encephalopathy diagnosed and managed? Elevated serum ammonia levels indicate hepatic encephalopathy in patients with cirrhosis and altered mental status that cannot be explained by any other cause. Precipitating factors include gastrointestinal bleeding, infection, constipation, and metabolic disturbances.

90. Treatment focuses on Reducing intestinal production of ammonia Typically through the use of cathartics (such as lactulose ) and antibiotics (such as neomycin and rifaximin ). Low-protein diets are no longer recommended as they do not appear to be effective at reducing encephalopathy and may contribute to malnutrition.

91. The pulmonary syndromes associated with chronic liver disease. Hepatopulmonary syndrome Is a mismatch of ventilation and perfusion that results primarily from :

92. Vasodilation of pulmonary capillaries . Arteriovenous communication in the lungs and pleura may occur as well. It is characterized by hypoxia and dyspnea that worsen with upright position ( orthodeoxia and platypnea , respectively).

93. Portopulmonary hypertension Is the development of Pulmonary hypertension in the presence of Portal hypertension.

94. When should patients with cirrhosis be referred for liver transplantation? Patients with cirrhosis should be referred for transplantation when they have their first major complication ( ascites , variceal bleeding, hepatic encephalopathy) or evidence of significant Hepatic dysfunction

95. Describe the pulmonary syndromes associated with chronic liver disease. Hepatopulmonary syndrome is a mismatch of ventilation and perfusion that results primarily from vasodilation of pulmonary capillaries . Arteriovenous communication in the lungs and pleura may occur as well. It is characterized by hypoxia and dyspnea that worsen with upright position ( orthodeoxia and platypnea , respectively). Portopulmonary hypertension is the development of pulmonary hypertension in the presence of portal hypertension. When should patients with cirrhosis be referred for liver transplantation? Patients with cirrhosis should be referred for transplantation when they have their first major complication ( ascites , variceal bleeding, hepatic encephalopathy) or evidence of significant hepatic dysfunction

96. GOOD LUCK SAMIR EL ANSARY ICU PROFESSOR AIN SHAMS CAIRO [email protected]