Chapter 18 part 2: infectious disorders Flashcards
1
Q
Types of infectious disorders of the liver
A
- Viral Hepatitis: A, B, C, D, E
- Bacterial, Parasitic and Helminthic infections
2
Q
Systemic viral infections that can involve the liver
A
- Epstein-Barr virus
- CMV
- Yellow fever virus
- Less commonly: rubella, adenovirus, enterovirus, herpesvirus
3
Q
Unless specified, hepatitis refers only to what kind of infections??
A
- infections of the liver by the hepatotropic viruses: A, B, C, D, or E!!!
- All produce similar clinical and morphological patterns of acute hepatitis but vary in their routes of transmission and potential to induce carrier states or chronic disease
4
Q
Hepatitis A virus
A
- ssRNA that causes a benign, self limited disease
- fulminant HAV is rare (0.1-0.3% fatality)
- not directly cytopathic
- hepatocyte damage is due to CD8+ T cell responses
- Accounts for 25% of acute hepatitis in world
- Acute infxn marked by anti HAV IgM in serum; IgG appears as IgM declines (in few months) and persists for years conferring long-term immunity
- vaccine available
5
Q
Hep B virus can cause:
A
- Acute, self-limited hepatitis
- Nonprogressive chronic hepatitis
- Progressive chronic disease culminating in cirrhosis and increased risk of HCC
- Fulminant hepatitis with massive liver necrosis
- Asymptomatic carrier state
6
Q
Potential outcomes of Hep B infection in adults and frequencies
A
- Acute infection–>subclinical dz (65), acute hepatitis (25), chronic hepatitis (5-10)
- Subclinical dz–>recovery (100)
- Acute hepatitis–>Recovery (99) or Fulminant Hep (<1)–>death or transplant
- Chronic hep–>HCC (2-3), cirrhosis (20-30), recovery
- cirrohhosis and HCC–>death or transplant
*acute hepatic failure and fulminant hep are same thing
7
Q
Major determinant of the outcome of Hep B infection is?
A
- Host immune response to virus
- Younger age at infection has higher probability of chronicity
- Innate immunity is protective during initial phases of infection and strong responses by virus-specific CD4+ and CD8+ interferon (IFN-y) producing cells are associated with resolution
- Abs prevent subsequent reinfection and form basis of effective vaccines
8
Q
How is hepatocyte killing mediated in HBV infection?
A
- HBV is not cytopathic
- hepatocyte killings is mediated by cytotoxic CD8+ T lymphocytes against virus-infected cells
- Viral DNA sequences can also integrate into host genomes, constituting a pathway for cancer development
9
Q
Structure of HBV
A
- ciruclar, partially DsDNA
- mature virus exists as a spherical “Dane particle” with outer surface protein and lipid envelop encasing an electron dense core
- 8 viral genotypes with distinct global distributions
- HBV genome has 4 open reading frames
10
Q
4 open reading frames of HBV
A
- Nucleocaspid core Ag (HBcAg) plus a longer polypeptide transcript (HBeAg) that is secreted into bloodstream
- Hep B surface Ag (HbsAg) envelope glycoproteins (large, middle and small); infected hepatocytes can synthesize and secrete massive quantities of noninfective HbsAg (mostly small HBsAg)
- Polymerase with both DNA polymerase and reverse transcriptase activity; viral replication occurs through an intermediate RNA template: DNA–>RNA–>DNA
- Hbx protein, a transcriptional transactivator of host and viral genes, necessary for viral replication
11
Q
HbsAg, HBe Ag and HBV DNA
A
- HbsAg appears before symptoms (anorexia, fever, jaundice)
- peaks during overt disease and declines over months
- HBeAg and HBV DNA appear soon after HBsAg and before disease onset
- HbeAg is detectable in serum during viral replication but some mutant strains do not produce it
- HbeAg usually declines within weeks
- persistence suggests progression to chronic disease
12
Q
Abs that appear in Hep infection
A
- IgM and anti-HBcAg are first to appear, followed by:
- anti-HbeAg and IgG anti-HBcAg
13
Q
Anti-HBSAg signifies
A
14
Q
Chronic carrier defined by
A
-presence of HBsAg in serum for 6 months
15
Q
Chronic Hep B infection Tx
A
-difficult to cure due to development of resistant mutant strains
16
Q
Hep B transmission–differences based on geography
A
- in high prevalence areas (Africa, Asia), transmission during childbirth=90%
- in intermediate prevalence regions (Southern and eastern europe), horizontal transmission in childhood by minor cutes or breaks in mucus membranes is most common
- in low prevalence areas (US and western Europe), IV drug abuse and unprotected intercourse are major modes of transmission
17
Q
Hep C Virus characteristics
A
- ssRNA, enveloped virus
- low fidelity of HCV RNA polymerase causes substantial genomic variability and constitutes a major obstacle to vaccine development–any person can harbor a population of related but divergent quasi species and the presence of high titers of anti-HCV IgG does not confer effective immunity
18
Q
Viral replication of Hep C virus
A
- begins with translation of a single polypeptide that is processed into nucleocapsid protein, envelope proteins and seven nonstructural proteins
- E2 envelope protein is a target of several anti-HCV Abs but is also the most variable region of genome allowing escape from otherwise neutralizing titers
- Anti-HCV Abs do not confer protection
19
Q
characteristic feature of HCV infection
A
-repeated bouts of damage
20
Q
difference bw HCV infection and HBV infection
A
- In contrast to HBV, progression to chronic disease occurs in most (80-90%) of HCV infected patients and cirrhosis occurs in 20%
- Like HBV hepatocellular damage is immune mediated, although the cellular immune responses are largely unable to completely eradicate HCV infections
21
Q
Incidence of HCV infection
A
- half of U.S burden of chronic liver dz
- incidence has significantly declined as a result of blood supply screening
22
Q
What ppl are at risk for HCV infection?
A
-Primary=IV drug abusers and multiple sexual partners
23
Q
Dx of HCV infection
A
- HCV RNA detectable in blood for 1-3 weeks during active infection, coincident with transaminase elevations
- Anti-HCV Abs occur in only 50-70% of patients in acute setting although 90% will eventually develop such Abs
24
Q
Treatment for chronic HCV infection
A
- potentially curable
- older Tx=IFN-a and ribovarin
- newer drugs that target viral protease and polymerase can achieve undetectable levels of virus in majority of pts
25
Q
Hep D virus
A
- defective RNA virus that can replicate and cause infection ONLY when encapsulated by HBsAg
- so ONLY develops when there is confection by HBV infection
- Acute confection by HDV and HBV leads to hepatitis that ranges from mild to fulminant but chronicity rarely develops
- BUT HDV SUPERINFECTION of an unrecognized HBV carrier or in a pt with chronic HBV leads to eruption of acute hepatitis with frequent conversion to chronic disease and cirrhosis
26
Q
High prevalence areas for HDV coinfection
A
- Africa
- Middle East
- Italy
- Amazon basin
- *UNCOMMON in US, Southeast Asia and China
27
Q
structural features of HDV
A
- has an HBV envelope
- the only protein produced by virus is an internal polypeptide assembly called the delta Ag (HDAg) associated with small circular ssRNA
- Viral replication requires host RNA polymerase activity
28
Q
HDV Dx
A
- HDV RNA appears in blood and liver before and ruing early acute symptomatic infection
- IgM anti-HDV indicates recent HDV exposure
- IgM anti-HbcAg suggests acute HBV confection whereas serum HBsAg implies superinfection
- Vaccination against HBV can prevent HDV infection
29
Q
Hep E virus
A
- nonenveloped ssRNA virus
- enterically transmitted, water-borne infection with several animal reservoirs (monkeys, cats, pigs, and dogs)
- HEV epidemics have occurred in Asia, Mexico, and Africa and also endemic in India where 30-60% of acute hepatitis cases
- typically self-limited with no chronicity but high rate of fatal fulminant hepatitis (20%) in pregnant women
30
Q
Hep E–Dx
A
- HEV Ag found in hepatocytes during active infection and visions and RNA can be detected in stool and serum before symptom onset
- Subsequent development IgG anti-HEV confers long-lived protection against reinfection
31
Q
Clfinicopathologic syndromes of viral hepatitis
A
- any hep virus can be asymptomatic or symptomatic
- fulminant course uncommon
- serologic and molecular studies essential for viral hep Dx and to distinguish type
- Acute asymptomatic infection with recovery, Acute symptomatic infection with recovery, Acute liver failure
32
Q
Acute asymptomatic infection with recovery
A
- Pts identified only incidentally based on elevated transaminases or by antiviral Ab titers
- HAV and HBV are frequently subclinial
33
Q
Acute symptomatic infection with recovery
A
- Acute symptomatic infections are all similar with variable incubation pds, asymptomatic preicteric phase, symptomatic icteric phase, and convalescence
- Peak infectivity occurs during last asymptomatic days of incubation pd and early days of acute symptoms
34
Q
Acute liver failure
A
- Viral hepatitis causes 10% of cases of acute hepatic failure; globally hep A and E are the most common causes whereas HBV is more common in Asian and Mediterranean countries
- Survival for more than a week may allow residual hepatocyte replication and activation of stem and progenitor cells yields prominent ductular reactions; recovery depends on restoration of missing parenchyma
- Care is supportive and liver transplantation is only option when disease does not resolve
35
Q
Chronic hepatitis
A
- symptomatic (fatigue, malaise, jaundice), biochemical or serologic evidence of ongoing hepatic disease for >6 months
- Acute HCV infxn progresses to chronic hepatitis in 80%–1/3 develop cirrhosis
- In addition to ongoing liver injury and risk of cirrhosis and/or HCC, immune complex disease (due to circulating Ab-Ag complexes) may develop w/vasculitis and glomerulonephritis
- 35% of chronic hep C pts develop cryoglobulinemia
36
Q
Carrier state
A
- A carrier harbors and can transmit hepatitis but has no manifest symptoms
- includes patients with chronic disease but few or no symptoms and those with little or no adverse effects (healthy carriers); for HBV, healthy carriers lack HBe Ag but have anti-HBeAg, normal serum aminotransferase levels, low serum HBV DNA and a liver biopsy without significant necrosis or inflammation
- In the US, adult HBV rarely produces a healthy carrier state but >90% of HBV infections acquired early in life in endemic areas result in healthy carrier state
37
Q
HIV and chronic viral hepatitis
A
- similar transmission modes and risks result in frequent HIV and hepatitis virus confections
- 10% of HIV patients are infected with HBV and 30% with HCV resulting in more aggressive liver disease
- Chronic hepatitis is a major cause of morbidity and mortality in HIV infected patients and liver disease is the 2nd most common cause of death in AIDS
38
Q
Morphology of acute and chronic hepatitis–general
A
- All hepatotropic viruses share most of the same morphologic changes
- features are nonspecific and can be mimicked by drug reaction or autoimmune liver disease but some distinct features may be present (HBV, HCV)
39
Q
HBV morphology
A
-infected hepatocytes can show a finely granular “ground glass” cytoplasm packed with HBsAg
40
Q
HCV morphology
A
-portal lymphoid aggregates, bile duct reactive changes and lobular regions of macro vesicular steatosis
41
Q
Acute hepatitis morphology
A
- Injured hepatocytes are eosinophilic and rounded with shrunken or fragmented nuclei (apoptosis) or swollen (ballooning degeneration)
- In severe hepatitis, confluent damage causes bridging necrosis between portal and central regions of adjacent lobules; cholestasis can occur
- Kupffer cell hyperplasia and macrophage aggregates mark the site of hepatocyte loss
- Portal tracts exhibit mononuclear cell inflammation often with spillover into adjacent parenchyma associated with periportal apoptosis (interface hepatitis)
42
Q
Chronic hepatitis morphology
A
- Histology ranges from mild to severe to cirrhosis
- Mild: inflammatory infiltrates only in portal tracts
- Progressive disease: extension of chronic inflammation from portal tracts with interface hepatitis; linking of portal-portal and portal-central regions constitutes bridging necrosis
- continued loss of hepatocytes results in fibrous septum formation!! Associated hepatocyte regeneration results in cirrhosis
43
Q
Bacterial, Parasitic and Helminthic Infections–Extrahepatic infections
A
-especially sepsis can induce hepatic inflammation and varying degrees of cholestasis
44
Q
Bacterial, Parasitic and Helminthic Infections–Biliary obstruction and intrabiliary bacterial proliferation
A
-can cause severe acute inflammatory response (ascending cholangitis)
45
Q
Bacterial, Parasitic and Helminthic Infections–parasitic infections
A
- e.g., amebic, echinococcal, malarial or helminthic organisms–are common causes of hepatic abscesses in developing countries
- Liver flukes most common in southeast Asi case a high rate of CCA
46
Q
Bacterial, Parasitic and Helminthic Infections–Abscesses occurring in developed countries
A
- rare; usually bacterial or candidal
- sources are intra-abdominal (via portal vein), systemic (via arterial supply), biliary tree, direct extension, and penetrating injuries
- Abscesses are associated with fever, right upper quadrant pain, tender hepatomegaly, and possibly jaundice
- Mortality without daringe is 90%; survival is dramatically improved by early Tx
- Rupture of echinococcal cysts can precipitate systemic spread of organism with severe immune mediated shock
