Hepatitis Flashcards
Incubation of HAV
2 to 6 weeks
What is the typical sequelae of HAV?
HAV does not cause chronic hepatitis or a carrier state and only uncommonly causes acute hepatic failure
HAV fatality rate
0.1-0.3%
HAV symptoms
nonspecific symptoms such as fatigue and loss of appetite, and often develop jaundice
Where is HAV most prevalent in the world?
occurs throughout the world and is endemic in countries with poor hygiene and sanitation.
HAV family and genotype
HAV is a small, nonenveloped, positive-strand RNA picornavirus of the genus, Hepatovirus
Structure of HAV?
HAV is an icosahedral capsid 27 nm in diameter
How is HAV spread?
HAV is spread by ingestion of contaminated water and foods and is shed in the stool for 2 to 3 weeks before and 1 week after the onset of jaundice. Thus, close personal contact with an infected individual or fecal-oral contamination during this period accounts for most cases and explains the outbreaks in institutional settings such as schools and nurseries, and the water-borne epidemics in places where people live in overcrowded, unsanitary conditions.
Is there a HAV vaccine?
Yes
What is the most likely reason for persons in developed country for contracting HAV?
consumption of raw or steamed shellfish (oysters, mussels, clams), which concentrate the virus from seawater contaminated with human sewage.
Describe the temporal changes in serological markers in acute HAV
http://tinyurl.com/zf3hvhu
Specific IgM antibody against HAV appears with the onset of symptoms
Fecal shedding of the virus ends as the IgM titer rises
he IgM response usually begins to decline in a few months and is followed by the appearance of IgG anti-HAV
The latter persists for years, perhaps conferring lifelong immunity against reinfection by all strains of HAV
What is the most reliable marker of acute HAV infection?
Specific IgM
Are there routinely available tests for IgG anti-HAV?
No, the presence of IgG anti-HAV is inferred from the difference between total and IgM anti-HAV.
What are the clinical sequelae for HBV?
(1) acute hepatitis followed by recovery and clearance of the virus,
(2) nonprogressive chronic hepatitis,
(3) progressive chronic disease ending in cirrhosis (or hepatocellular carcinoma without cirrhosis),
(4) acute hepatic failure with massive liver necrosis, and
(5) an asymptomatic, “healthy” carrier state.
In almost all cases the infection is self-limited and resolves without treatment. Chronic disease occurs in 5%-10% of infected individuals. Fulminant hepatitis (acute hepatic failure) is rare, occurring in approximately 0.1% to 0.5% of acutely infected individuals.
What determines the chronicity of HBV infection?
age at infection
The younger the age at the time of HBV infection, the higher the probability of chronicity.
How is HBV transmitted in different geographical areas?
In high prevalence regions of the world, transmission during childbirth accounts for 90% of cases.
In areas with intermediate prevalence, horizontal transmission, especially in early childhood, is the dominant mode of transmission (minor breaks in the skin or mucous membranes among children with close bodily contact).
In low prevalence areas, unprotected sex and intravenous drug abuse (sharing of needles and syringes) are the chief modes of spread.
What is the incubation period of HBV?
2 to 26 weeks
HBV remains in the blood until and during active episodes of acute and chronic hepatitis.
Symptoms of HBV
Approximately 65% of adults newly acquiring HBV have mild or no symptoms and do not develop jaundice.
The remaining 25% have nonspecific constitutional symptoms such as anorexia, fever, jaundice, and upper right quadrant pain.
What is the family and virus type of HBV?
Hepadnaviridae, a family of DNA viruses that cause hepatitis in multiple animal species.
of HBV genotypes in the world?
8
What is the structure of HBV?
42-nm, spherical double-layered “Dane particle” that has an outer surface envelope of protein, lipid, and carbohydrate enclosing an electron-dense, 28-nm, slightly hexagonal core.
Describe the genome of HBV
partially double-stranded circular DNA molecule having 3200 nucleotides with 4 open reading frames coding for:
- A nucleocapsid “core” protein (HBcAg, hepatitis B core antigen) and a longer polypeptide transcript with a precore and core region, designated HBeAg (hepatitis B e antigen). The precore region directs the secretion of the HBeAg polypeptide, whereas HBcAg remains in hepatocytes, where it participates in the assembly of complete virions.
- Envelope glycoproteins (HBsAg, hepatitis B surface antigen), which consist of three related proteins: large, middle, and small HBsAg. Infected hepatocytes are capable of synthesizing and secreting massive quantities of noninfective surface protein (mainly small HBsAg).
- A polymerase (Pol) that exhibits both DNA polymerase activity and reverse transcriptase activity. Replication of the viral genome occurs via an intermediate RNA template, through a unique replication cycle: DNA → RNA → DNA
- HBx protein, which is necessary for virus replication and may act as a transcriptional transactivator of both viral genes and a subset of host genes. It has been implicated in the pathogenesis of hepatocellular carcinoma in HBV infection.
Describe the natural course of disease by serological markers
HBsAg appears before the onset of symptoms, peaks during overt disease, and then often declines to undetectable levels in 12 weeks, although it may persist in some individuals for as long as 24 weeks.
Anti-HBs antibody does not rise until the acute disease is over, concomitant with the disappearance of HBsAg.
serologic diagnosis can be made by detection of IgM anti-HBc antibody
Anti-HBs may persist for life, conferring protection; this is the basis for current vaccination strategies using noninfectious HBsAg.
HBeAg, HBV-DNA, and DNA polymerase appear in serum soon after HBsAg, and all signify active viral replication.
IgM anti-HBc antibody becomes detectable in serum shortly before the onset of symptoms, concurrent with the onset of elevated serum aminotransferase levels (indicative of hepatocyte destruction).
Over a period of months the IgM anti-HBc antibody is replaced by IgG anti-HBc. As in the case of anti-HAV, there is no direct assay for IgG anti-HBc; its presence is inferred from decline of IgM anti-HBc in the face of rising total anti-HBc.
What serological antigens signify active viral replication?
HBeAg
HBV-DNA
What marker is an indicator of continued viral replication, infectivity, and probable progression to chronic hepatitis?
HBeAg
What does anti-HBe antibodies imply?
an acute infection has peaked and is on the wane.
What is the main determinant of the outcome of HBV infection?
The host immune response to the virus
Innate immune mechanisms protect the host during the initial phases of the infection, and a strong response by virus-specific CD4+ and CD8+ interferon (IFN)-γ–producing cells is associated with the resolution of acute infection.
What causes hepatocyte injury in HBV infections?
HBV generally does not cause direct hepatocyte injury. Instead, injury is caused by CD8+ cytotoxic T cells attacking infected cells.
What makes HBV so persistent?
The difficulty in achieving cure has been attributed to the ability of the virus to insert itself in the host DNA, thus limiting the development of an effective immune response (HBsAb development)
What is the goal of treatment of chronic HBV infection?
slow disease progression, reduce liver damage, and prevent liver cirrhosis or liver cancer.
Is the HBV vaccine effective in infants and children?
Vaccination induces a protective anti-HBs antibody response in 95% of infants, children, and adolescents.
What are the risk factors for HCV infection?
- Intravenous drug abuse (54%)
- Multiple sex partners (36%)
- Having had surgery within the last 6 month (16%)
- Needle stick injury (10%)
- Multiple contacts with an HCV-infected person (10%)
- Employment in medical or dental fields (1.5%)
- Unknown (32%) - 1/3 of people have no identifiable risk factors
What is the major route of infection for children?
perinatal, but this route of infection with HCV is much lower than for HBV (6% vs. 20%).
HCV genotype and family
member of the Flaviviridae family.
It is a small, enveloped, single-stranded RNA virus with a 9.6-kilobase (kb) genome that codes for a single polyprotein with one open reading frame, which is subsequently processed into functional proteins.
Why does HCV exists as quasispecies in any individual?.
Low fidelity of the HCV RNA polymerase, the virus is inherently unstable, giving rise to multiple genotypes and subtypes.
What protein is are anti-HCV antibodies targeted towards?
The E2 protein of the envelope is the target of many anti-HCV antibodies but is also the most variable region of the entire viral genome, enabling emergent virus strains to escape from neutralizing antibodies.
Is a HCV vaccine available?
No, due to genomic instability and antigenic variability
elevated titers of anti-HCV IgG occurring after an active infection do not confer effective immunity
What is the incubation period of HCV?
4 to 26 weeks, with a mean of 9 weeks.
What are two characteristic feature of HCV infection?
repeated bouts of hepatic damage, the result of reactivation of a preexisting infection or emergence of an endogenous, newly mutated strain, despite the generally asymptomatic nature of acute illness
persistent elevations in serum aminotransferases. Their levels wax and wane but almost never become normal. Even rare patients with normal transaminases are at risk for developing permanent liver damage.
What is the most common clinical sequelae of acute HCV infection?
In about 85% of individuals, the clinical course of the acute infection is asymptomatic and typically missed. The clinical course of acute HCV hepatitis is milder than that of HBV; rare cases may be severe and indistinguishable from HAV or HBV hepatitis.
Describe the serological antibody response to HCV infections.
HCV RNA is detectable in blood for 1 to 3 weeks, coincident with elevations in serum transaminases. In symptomatic acute HCV infection, anti-HCV antibodies are detected in only 50% to 70% of patients; in the remaining patients, the anti-HCV antibodies emerge after 3 to 6 weeks.
In contrast to HBV, chronic disease occurs in the majority of ________-infected individuals (80% to 90%) and _______ eventually occurs in as many as a 20% of individuals with ________ infection.
HCV
cirrhosis
chronic HCV
What is the mechanism of HCV pathology?
HCV is able to actively inhibit the IFN-mediated cellular antiviral response at multiple steps, including toll-like receptor signaling in response to viral RNA recognition and signaling downstream of IFN receptors that would otherwise have antiviral effects.
Why must HCV RNA testing must be performed to assess viral replication and to confirm the diagnosis of HCV infection in persons with chronic hepatitis?
In more than 90% of individuals with chronic HCV infection, circulating HCV RNA persists despite the presence of antibodies
What feature is unique to hepatitis C infection?
association with metabolic syndrome (HCV can give rise to insulin resistance and non alcoholic fatty liver disease.)
Is HCV curable?
If yes, with what?
Potentially.
Treatment has been based on combination of pegylated IFN-α and ribavirin and cure rates depended on the viral genotype but host genotype also influences the response.
What is “the delta agent” and why?
hepatitis D virus (HDV) is a unique RNA virus that is dependent for its life cycle on HBV.
What is co-infection of HDV?
Co-infection occurs following exposure to serum containing both HDV and HBV. The HBV must become established first to provide the HBsAg necessary for development of complete HDV virions.
What is the result of co-infection of HDV and HBV?
acute hepatitis that is indistinguishable from acute hepatitis B.
It is self -limited and is usually followed by clearance of both viruses. However, there is a higher rate of acute hepatic failure, in intravenous drug users.
What is superinfection of HDV?
chronic carrier of HBV is exposed to a new inoculum of HDV.
What is the result of superinfection of HDV and HBV?
disease 30 to 50 days later presenting either as severe acute hepatitis in a previously unrecognized HBV carrier or as an exacerbation of preexisting chronic hepatitis B infection.
What are the two phases of superinfection?
acute phase with active HDV replication and suppression of HBV with high transaminase levels
chronic phase in which HDV replication decreases, HBV replication increases, transferase levels fluctuate, and the disease progresses to cirrhosis and sometimes hepatocellular carcinoma.
How does HDV replicate?
RNA-directed RNA synthesis by host RNA polymerase
Describe he genome structure of HDV
35-nm, double-shelled particle.
The external coat antigen of HBsAg surrounds an internal polypeptide assembly, designated delta antigen (HDAg), the only protein produced by the virus
What is the most reliable indicator of HDV exposure?
IgM anti-HDV antibody
although its appearance is late and frequently short-lived.
What is detected in the blood and liver just before and in the early days of acute HDV asymptomatic disease?
HDV RNA
What is the most reliable indicator of co-infection by HDV and HBV?
IgM against both HDAg and HBcAg (denoting new infection with hepatitis B)
What is the most reliable indicator of superinfection by HDV and HBV?
HBsAg is present in serum, and anti-HDV antibodies (IgG and IgM) persist for months or longer.
What prevents HDV infection?
Vaccination for HBV
How is HEV transmitted?
enterically transmitted, water-borne infection
What is the most likely population to be infected with HEV?
young to middle-aged adults.
What is HEV?
zoonotic disease with animal reservoirs, such as monkeys, cats, pigs, and dogs (pig farming)
What is a characteristic feature of HEV infection?
High mortality rate among pregnant women, approaching 20%
What is the clinical sequelae of HEV infection?
In most cases the disease is self-limiting; HEV is not associated with chronic liver disease or persistent viremia in immunocompetent patients.
Chronic HEV infection does occur in patients with AIDS and immunosuppressed transplant patients.
Average incubation time for HEV
4 to 5 weeks.
Describe the genome and structure of HEV
Viral particles are 32 to 34 nm in diameter, and the RNA genome is approximately 7.3 kb in size. unenveloped, positive-stranded RNA virus in the Hepevirus genus.
How are virions shed?
in stool during the acute illness.
How can HEV infection be detected?
Before the onset of clinical illness, HEV RNA and HEV virions can be detected by PCR in stool and serum.
The onset of rising serum aminotransferases, clinical illness, and elevated IgM anti-HEV titers are virtually simultaneous.
Symptoms resolve in 2 to 4 weeks, during which time the IgM is replaced with a persistent IgG anti-HEV antibodies.
Which Hepatitis viruses can cause acute infections?
All of the hepatotropic viruses can cause acute asymptomatic or symptomatic infection.
T/F HEV causes chronic infection.
HAV and HEV (in immunocompetent hosts) do not cause chronic hepatitis
Which hepatitis virus causes chronic infection?
HBV can cause chronic infection.
HCV is notorious for chronic infection.
T/F HEV can cause fulminant hepatitis in pregnant women.
T.
Fulminant hepatitis (acute liver failure) is unusual and is seen primarily with HAV, HBV, or HDV infection depending on region.
What does it mean when patients have Acute Asymptomatic hpepatitis Infection with Recovery?
Patients in this group are identified only incidentally on the basis of minimally elevated serum transaminases or, after the fact, by the presence of antiviral antibodies.
i.e. Worldwide, HAV and HBV infection are frequently subclinical events in childhood, verified only in adulthood by the presence of anti-HAV or anti-HBV antibodies.
Describe the 4 phases of “Acute Symptomatic hepatitis Infection with Recovery”
Regardless of the virus, the disease is more or less the same and can be divided into four phases:
(1) an incubation period,
(2) a symptomatic preicteric phase,
(3) a symptomatic icteric phase, and
(4) convalescence.
Peak infectivity occurs during the last asymptomatic days of the incubation period and the early days of acute symptoms.
What is the result of acute liver failure?
Survival for more than a week may permit the replication of residual hepatocytes.
recovery depends on surviving hepatocytes undergoing cell division to restore missing parenchyma .
The treatment for acute hepatic failure that follows acute viral hepatitis is to provide supportive care.
Liver transplantation is the only option for patients whose disease does not resolve before secondary infection and other organ failure develop.
What is the most common cause of Acute liver failure?
Globally, hepatitis A and E are the most common causes; HBV is more common in Asian and Mediterranean countries
How is acute liver failure histologically identified?
Morphologic details of massive necrosis
There are no specific histologic findings which are indicative of hepatotropic virus causation.
What is chronic hepatitis?
symptomatic, biochemical, or serologic evidence of continuing or relapsing hepatic disease for more than 6 months
What are the typical clinical features of chronic hepatitis?
persistent elevations of serum transaminases
prolongation of the prothrombin time
hyperglobulinemia
hyperbilirubinemia
mild elevations in alkaline phosphatase levels.
What are the symptoms of chronic hepatitis?
fatigue;
malaise, loss of appetite, and occasional bouts of mild jaundice
What are the clinical findings of chronic hepatitis?
In precirrhotic chronic hepatitis, physical findings are few, the most common being mild hepatomegaly, hepatic tenderness, and mild splenomegaly.
Describe a carrier state of hepatitis infections.
(1) individuals who carry one of the viruses but have no liver disease;
(2) those who harbor one of the viruses and have non-progressive liver damage, but are essentially free of symptoms or disability.
Describe a carrier of HBV infection.
an individual with HBsAg, without HBeAg, but with presence of anti-HBe; these patients have normal aminotransferases, low or undetectable serum HBV DNA, and a liver biopsy showing a lack of significant inflammation and necrosis
N.B. It should be kept in mind that “healthy carrier” is probably not a stable state and that re-activation of hepatitis can occur in response to co-infection or alterations of immune function related to age or co-morbid diseases
Why is HIV and hepatitis viruses a common medical problem?
similar transmission mode and the similar high-risk patient population
What is the relationship between HIV and hepatitis infections?
chronic HBV and HCV infection are now leading causes of morbidity and mortality for HIV-infected individuals, even those who are on successful anti-HIV therapy.
What are the histological/morphological features of a liver with acute viral hepatitis?
Portal inflammation in acute hepatitis is minimal or absent. Most parenchymal injury is scattered throughout the hepatic lobule as “spotty necrosis” or lobular hepatitis
confluent necrosis of hepatocytes is seen around central veins.
In these areas there may be cellular debris, collapsed reticulin fibers, congestion/hemorrhage, and variable inflammation.
With increasing severity, there is central-portal bridging necrosis, followed by, even worse, parenchymal collapse
In occasional cases, the injury is not severe enough to cause death (or necessitate transplantation), and the liver survives, although with abundant scarring, usually with replacement of areas of confluent necrosis. In such cases, some patients rapidly develop posthepatitic cirrhosis.
What is a gross feature of a liver with acute viral hepatitis?
On gross inspection, livers involved by mild acute hepatitis appear normal or slightly mottled. At the other end of the spectrum, in massive hepatic necrosis the liver may shrink greatly
What is lobular hepatitis?
apoptotic/necrotic hepatocytes that is scattered throughout the hepatic lobule and appears as ‘spotty necrosis’
Apoptosis of hepatocytes: hepatocytes shrink, becoming intensely eosinophilic, and their nuclei become pyknotic and fragmented; effector T cells may be present in the immediate vicinity
Necrosis of hepatocytes: the cytoplasm appears empty with only scattered wisps of cytoplasmic remnants. Eventually there is rupture of cell membranes leading to “dropout” of hepatocytes, leaving collapsed sinusoidal collagen reticulin framework behind; scavenger macrophages mark sites of dropout
What is the defining histologic feature of chronic viral hepatitis?
mononuclear portal infiltration.
What is interface hepatitis?
distinguished by its location at the interface between hepatocellular parenchyma and portal tract stroma.
What is the hallmark of progressive chronic liver damage?
scarring
At first, only portal tracts exhibit fibrosis, but in some patients, with time, fibrous septa—bands of dense scar—extend between portal tracts.
increasing ductular reaction, reflecting stem cell activation. In the most severe cases, continued scarring and nodule formation leads to the development of cirrhosis
What are ground-glass” hepatocytes and in which condition does it surface?
chronic hepatitis B
cells with endoplasmic reticulum swollen by HBsAg
confirm HBsAg with Immunostaining
What is a common histologial feature of chronic HCV infection?
lymphoid aggregates or fully formed lymphoid follicles
fatty change of scattered hepatocytes, although the infection may also cause systemic alterations leading to metabolic syndrome and, therefore, a superimposed non-alcoholic fatty liver disease in the liver
Bile duct injury
What bacteria can infect the liver directly?
Staphylococcus aureus in toxic shock syndrome, Salmonella typhi in typhoid fever
Treponema pallidum in secondary or tertiary syphilis
What are the symptoms of liver abscesses?
fever, right upper quadrant pain and tender hepatomegaly.
Jaundice may result from extrahepatic biliary obstruction.
What is autoimmune hepatitis?
chronic, progressive hepatitis with all the features of autoimmune diseases in general: genetic predisposition, association with other autoimmune diseases, presence of autoantibodies, and therapeutic response to immunosuppression.
frequent association with DRB1* alleles and female dominance.
What are the two types of autoimmune hepatitis (classified according on the patterns of circulating antibodies) ?
Type 1 autoimmune hepatitis is most often seen in middle-aged women and is most characteristically associated with antinuclear and anti–smooth muscle antibodies (ANA and ASMA)
Type 2 autoimmune hepatitis is most often seen in children or teenagers and is associated with anti-liver kidney microsomal autoantibodies (anti-LKM1)
What is the likely course of autoimmune hepatitis?
either develop with a rapidly progressive acute disease or follow a more indolent path; if untreated, both are likely to lead to liver failure.
What is a prominent and characteristic component of the inflammatory infiltrate in autoimmune hepatitis?
plasma cells
What should always be included in the differential diagnosis of any form of liver disease?
Exposure to a toxin or therapeutic agent (drug- and toxin-induced liver injury)
What is the most common hepatotoxin causing acute liver failure?
acetaminophen (paracetamol)
