11-30 Liver Pathology 2 Flashcards
What are some categories of causes for liver injury?
Infectious
Immune mediated
Drug and Toxins
Metabolic
Genetic
Autoimmune Cholangiopathy
What are some infectious causes of liver injury?
Viral hepatitis - A, B, C, D, E
Give some examples of immune-mediated, drug and toxin, metabolic, genetic, and autoimmune cholangiopathy causes of liver injury.
•Infectious
–Viral hepatitis (A, B, C, D, E, ???)
•Immune Mediated
–Autoimmune hepatitis
•Drug and Toxin
–Acetaminophen
–Ethanol
•Metabolic
–Non-alcoholic fatty liver disease
•Genetic
–Hemochromatosis
–Wilson’s disease
–Alpha-1 antitrypsin deficiency
•Autoimmune Cholangiopathy
–Primary biliary cirrhosis
–Primary sclerosing cholangitis
What are the various clinicopathological syndromes of viral hepatitis?
- Acute asymptomatic infection with recovery (serologic evidence only)
- Acute symptomatic hepatitis with recovery
- Chronic hepatitis, with or without progression to cirrhosis
- Acute liver failure with massive to submassive hepatic necrosis
What parts of the hepatitis viruses can be tested for to determine infection status?
Ab to viral proteins
Viral proteins
Viral nucleic acid
Which Ab titers to hepatitis viral proteins are tested? What is the timeframe for a postive result?
•Antibody to viral proteins (often coat proteins) take day-weeks to develop (delay)
–IgM - initial response to acute infection
–IgG - long term response
- ongoing chronic infection
- past infection
How are viral proteins tested for hepatitis infection?
•Viral proteins
–rarely measurable
–exception: Hepatitis B
How is viral nucleic acid tested for hepatitis infection? Is this an accurate testing method?
•Viral nucleic acid
–Polymerase chain reaction assays available
–most infections will be diagnosed by detection of organism nucleic acid in the future
What is the typical course of an acute viral hepatitis in terms of:
viral replication
aminotransferase elevations
bilirubin elevations
fatigue/malaise
nausea/anorexia
What does icteric mean?
jaundice
In an acute viral hepatitis infection, what causes most of the damage to host hepatocytes?
Host immune system - hepatitis viruses are not directly cytopathic
What does acute hepatitis lead to?
Infection with a hepatotropic virus causes an acute episode of liver inflammation, referred to as acute hepatitis, which can lead to either spontaneous clearance of the infectious agent or its persistence, which in turn leads to chronic infection for a subset of these viruses.
What is the incubation period for a hepatitis viral infection? What are the symptoms?
Incubation period (Days to weeks) is generally characterized by nonspecific symptoms,
including fatigue, nausea, loss of appetite, flulike symptoms, and/or right upper quadrant pain
What are the immune-mediated symptoms in viral hepatitis infection?
•Immune-mediated symptoms, including rash, hives, arthralgias, and fever, are observed in 10 to 20% of patients during the preicteric phase.
What do you make of this case:
30 year old woman with a 1 week history of:
increasing fatigue
nausea
loss of taste for meat, oily foods
1-2 days of darkening urine,
“yellow eyes”
PE: jaundice and moderately tender liver
Lab tests: CBC: normal
Bilirubin 5.0 mg/dl (nl <1.1)
AST 955 IU/ml (nl <45)
ALT 1125 IU/ml (nl<55)
Alk phos 250 IU/ml (nl <140)
Albumin 4.2 gm/dl (3.5<nl></nl>
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Typical case history for acute viral hepatitis
What is ALT? Where is it housed, and what is it indicative of?
•Serum alanine transaminase (ALT):
Liver cell cytosol
(ALT>AST = viral hepatitis)
What is AST? Where is it housed, and what does it indicate?
•Serum aspartate transaminase (AST):
Liver cell mitochondria
(AST>ALT = Alcoholic hepatitis)
Why does alcohol affect AST levels?
AST stored in liver cell mitochondria
EtOH toxic to mitochondria, synthesis of ALT decreased with EtOH
What is ALP? Where is it stored?
ALP = Alkaline Phosphatase
stored in bile duct epithelium
When is jaundice detected clinically?
once the serum bilirubin level rises above 3 mg per dL
What is jaundice the result of?
•from interference in the normal metabolism of bilirubin (including uptake, transport, conjugation and excretion)
What would you expect the urine and stool colors to be in a case of obstructive jaundice?
pale/clay colored stool or ‘fishes’
dark colored urine
What is the cause of pale fishes or dark urine in obstructive jaundice?
system backup and subsequent overload of urobilinogen
Describe the histological findings consistent with lobular disarray.
Lobular disarray
– Ballooned hepatocytes and acidophilic bodies
– Individual or confluent hepatocyte dropout
– Zonal, bridging, or panlobular necrosis
– Sinusoidal inflammatory cells
– Prominent Kupffer cells
What is lobular disarray a sign of?
Found in histology specimen of acute hepatitis
Would you expect to see inflammation or fibrosis in lobular disarray?
Mild portal inflammation
No fibrosis
What’s this? What is this specific for?
Hepatic triad on left shows minimal inflammation
lobular disarray present in lower right, with ballooned hepatocytes
Acute hepatitis looks remarkably similar in histo, differentiate via Ab titers or PCR
What type of virus is hepatitis A virus?
ssRNA
What is the time frame of a hepatitis A infection?
self-limited disease,
incubation period of 2 to 6 wks
Does hepatitis A cause chronic hepatitis?
•Does not cause chronic hepatitis or a carrier state in the immunocompetent patient
How is hepatitis A spread?
•Generally transmitted via the oral-fecal route, person to person/contaminated water and foods
When does blood-borne transmission of HAV occur?
rarely
What are some risk factors for hepatitis A infection?
What is the receptor for HAV?
•Receptor for HAV (Picornavirus) is an integral membrane glycoprotein receptor
What does the genome of HAV work as? (hint: it’s a +ssRNA)
•Genome serves as a messenger RNA that encodes both structural and nonstructural viral proteins
How is the genome of HAV translated?
•In the cytoplasm RNA translation into a polyprotein that is later processed to mature viral proteins
Where are new HAV virions excreted? Do they lyse the cell?
•Replication membrane-bound complex generates new viral genomes that are exported out of cell into bile and to a lesser extent into blood
- generally does not cause lysis of cell
Describe the rise and fall of IgM and IgG titers throughout the course of an acute HAV infection.
What is the pathogenesis of HAV?
During the period of viral replication in the liver cells the immune system mounts an attack on the virus; this immune response results in inflammation and liver cell injury (i.e. hepatitis)
What are the hepatitis viruses that only cause an acute self-limited disease?
•Hepatitis A
–RNA virus (picornavirus)
–Good vaccine available
•Hepatitis E
–RNA virus (Hepeviridae)
How is HEV transmitted?
•Hepatitis E virus (HEV) is an enterically transmitted, water-borne infection
When is HEV problematic?
•Feature of HEV infection is the high mortality rate among pregnant women, approaching 20%.
What is the typical infection with HEV?
•Typically acute, self-limited icteric disease without a chronic/carrier state, much like Hepatitis A
What lab tests are used for HEV?
•Laboratory Tests
–IgM antibody to hepatitis E for acute disease
–IgG antibody to hepatitis E for past disease or immunity
–
•Vaccine under development
What is the histopathology of HEV?
•Not much information on detailed histological appearances in hepatitis E.
–Focal hepatocyte necrosis including frequent acidophil bodies, swollen (or ballooned) hepatocytes, and lymphocytic parenchymal and portal infiltrates
–
–Canalicular cholestasis and gland-like transformation of hepatocytes.
What are hepatitis virsuse that cause both acute and chronic disease?
•Hepatitis B
•
•Hepatitis B + D
•
•Hepatitis C
What is HBV? How is it spread?
•DNA virus (Hepadnaviridae)
•
•Replicates through RNA intermediate (like HIV)
•
•Blood borne
•
•Many serologic tests have been developed
How do HBV infections develop?
•Spontaneous recovery in patients infected at birth is <5%
•
•Adult infections spontaneously resolve in
95-99%
•
•5-10% of infected individuals develop chronic disease
•
•Low prevalence areas (USA) unprotected sex and IV drug abuse are the chief modes of spread.
What are the clinical SSXs of HBV?
- Fatigue
- Anorexia
- Nausea
- Jaundice/Scleral icterus
- Abdominal pain
- Arthralgia
What are the potential outcomes of HBV infection in adults?
How has the rate of new HBV infections changed?
The rate of new HBV infections has declined by approximately 82% since 1991, when a national strategy to eliminate HBV infection was implemented in the United States. The decline has been greatest among children born since 1991, when routine vaccination of children was first recommended.
What does an HBV particle look like?
What are the virus compoenents that can be measured in HBV testing?
Virus components:
- viral DNA
- DNA polymerase (research test)
- s antigen (surface coat protein)
- e antigen (clipped portion of core protein)
What serum Ab can be tested in HBV infection?
Serum antibodies:
- Antibody to s (surface)
- Antibody to c (core)
- Antibody to e
What is the sequence of serological markers for HBV infection?
Left: acute hepatitis B viral infection with recovery
Right: acute hepatitis B viral infection with progression to chronic
What are the serologic markers for acute self-limited hepatitis B viral infection?
•In patients with acute hepatitis B, there is almost always an antibody response to HBcAg and usually an antibody response to HBsAg
•
•With the appearance of HBsAb, the patient becomes immune to a new HBV infection
What are the serological markers for chronic HBV infection?
•HBsAg appears in the serum in a similar time course, but does not abate, and antibody to HBsAg fails to develop.
•
•HBsAg in the blood is thus the hallmark of active current HBV infection, whether acute or chronic
What is the interpretation of serological markers for HBV infection?
HBsAg HBV infection (acute or chronic)
HBeAg High viral load/infectivity
HBV DNA High viral load/infectivity
Anti-HBs Immunity
Anti-HBc IgM Acute infection
Anti-HBc IgG Past or chronic infection
Anti-HBe Past or low infectivity chronic infection
Anti-HBc IgG and HBsAg Chronic infection
Anti-HBc IgG and anti-HBs Resolved (past) infection
What is the histopathology of HBV infection?
•Acute and chronic hepatitis B infection appear essentially similar to other forms of acute and chronic hepatitis
•
•Chronic HBV distinctive histological feature is the ‘ground-glass hepatocyte’ containing abundant HBsAg
What’s this?
•Ground-glass hepatocytes in chronic hepatitis B infection can be identified by the homogeneous pink cytoplasmic inclusions, which can be surrounded by a clear halo.
•
• The inclusion pushes the cytoplasmic contents and the nucleus to the sides of the cell. The inclusion represents endoplasmic reticulum filled with hepatitis B surface antigen
What are the hepatitis viruses that may cause both acute and chronic disease?
•Hepatitis B
•
•Hepatitis B + D
•
•Hepatitis C
How does HDV infect?
•Defective RNA virus that requires coinfection with Hepatitis B virus
How is HDV acquired and spread? What is the incidence?
•HBV surface antigen surrounds HDV
•
•Spread of HDV follows that of HBV, primarily through parenteral exposure
•
•It can either be acquired at the same time as a primary HBV infection or later, superimposed on a pre-existent chronic hepatitis B.
•
•HDV is rare in the USA and in other countries with a relatively low HBV incidence
What does the HDV particle look like?
Blue is Hep B surface antigen, constitutes the HDV coat protein
pink is HDV RNA
yellow is delta antigen
What is the most severe form of hepatitis? What does the infection progress to?
•Delta hepatitis is considered to be the most severe viral hepatitis. In acute forms it produces more fatalities. In chronic forms it produces more cirrhosis
•
•Most (50-70%) cases of superinfection develop a severe form of acute hepatitis and 90% of them become chronic carriers.
What is the histopathology of HDV infection?
•Acute and chronic hepatitis D infections look like any other acute or chronic hepatitis.
•
•Single distinguishing feature is the sanded nucleus due to HDAg accumulating in the nucleus of infected cells (looks like HBcAg in nucleus)
What’s this?
•Sanded nucleus in an infected cell can be seen associated with HDV antigens accumulating in the nucleus without HBcAg.
What are some hepatitis viruses that may cause both acute and chronic disease?
Hep C
What is the progress of a Hep C infection?
•Most common cause of chronic hepatitis world-wide, including USA
•
•In 85% of individuals, the clinical course of the acute infection is asymptomatic and typically missed
•
•Chronic infection can lead to cirrhosis and Hepatocellular carcnoma in up to 25%
What is the consistent clinical feature in HCV infection?
•Clinical feature that is quite characteristic of chronic HCV infection is persistent elevations in serum aminotransferases
What is the viral serology in HCV infection?
•In symptomatic acute HCV infection, anti-HCV antibodies are initially detected in only 50% to 70% of patients
•
• In the remaining patients, the anti-HCV antibodies emerge after 3 to 6 weeks.
What occurs in teh majority of HCV infected individuals?
•Chronic disease occurs in the majority of HCV-infected individuals (80% to 90%)
What about HCV lends it the ability to create a chronic infection?
•Small single-stranded RNA virus (described in 1989) which has an inherently unstable genome
What are the potential outcomes of Hep C infections in adults?
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%)
What are the typical levels of HCV RNA and serum transaminases throughout HCV infection?
What are the 2 modalities for testing HCV? When do they appear?
Hepatitis C IgG antibody
- Appears weeks after onset of new infection
- Signifies past resolved or chronic hepatitis C
- Occasional false positive
Hepatitis C RNA (by PCR)
- Signifies the virus is present in liver/blood
- Found in acute or chronic hepatitis C
What is the histopathology of HCV infection?
•Acute and chronic hepatitis C infection appear essentially similar to other forms of acute and chronic hepatitis
•
- Steatosis and bile duct damage may also be found.
- Asymptomatic patients, even those without serum aminotransferase elevations, may have significantly abnormal histology
What’s this?
Chronic Hep C
ex-IV drug user
What’s this?
Chronic HCV
Ex-IV drug user
What’s this?
chronic hep c
What’s this?
A bile duct shows disruption, intraepithelial mononuclear cells, and regenerative changes. Bile duct damage is commonly seen in chronic hepatitis C infections.
What is the Tx for hep c?
•New direct-acting oral agents capable of curing hepatitis C virus (HCV) infection have been approved for use in the United States.
•
•Effective hepatitis C medications cost $1,000 a pill and more than $100,000 for a full course of treatment
Summarize the clinicopathological features of viral hepatitis.
•Acute asymptomatic
–All of the hepatotropic viruses
•Acute symptomatic
–All of the hepatotropic viruses
–
•Acute liver failure
–Viral hepatitis is responsible for about 10% of cases of acute liver failure
–HAV, HEV and HBV, HDV
•Chronic hepatitis
–HCV >80%
–HBV <10% in adults (perinatal >90%)
–
•Carrier state
–Small number of HBV
–No HCV
What is the association between HIV and Hep C?
•10% of HIV-infected individuals are co-infected with HBV and 25% with HCV (USA)
•
•In patients with acquired immunodeficiency syndrome (AIDS), liver disease is the second most common cause of death
What is the breakdown between the different hepatitis viruses and acute and chronic hepatitis?
Hepatitis Viruses
Virus % Acute hepatitis (USA) % Chronic hepatitis
A ~30 0
B ~30 ~15
C ~30 (rarely detected) ~45+
D <5 ~5
E <1 0
Summarize transmission between all types of hepatitis viruses.
