Hepatisis Flashcards
What is the functional unit of the liver an dhow does this relate to blood flow/hepatitis
Lobule!
Blood enters from the triads, exits from the central vein
Most blood flows into the liver via the portal vein, which collects bloood from the entire GI tract
Remaining blood is oxygenated blood supplied by portal artery (20%)
These vessels continue to bifurcate—> small venues and arterioles ultimately terminating in the sinusoids which are small blood vessels with fenestrated endothelium (ie there are holes) that are lined by hepatocytes
These terminate in the central vein, from which the blood exits. A lobule has a central vein in the center, around which like spokes of a wheel are the portal traits. Each triad has a branch of the portal vein, a branch of the hepatic artery, and a small bile duct (triad)
Blood enters in the triad, flows through the sinusoids to the central vein, then exits the liver
Hepatocellular necrosis around the portal triad, where inflammation occurs not usually infectious because lots of things cause inflammation in the liver
What is hepatitis
Hepatic inflammation/injury
Hepatic cell necrosis (cell death)
May be acute or chronic; diverse etiologies;
- bacterial, fungal, parasitic infections
- immune disorders
- metabolic diseases
- lack of perfusion/oxygenation
- toxic injury (medications, toxins, herbals, alcohol)
- viral infections
Inflammation is around the portal triads
Many things can cause hepatitis, most not due to viral infection
Viral hepatitis
Numerous viruses can infect the liver
However the term viral hepatitis is reserved for those viruses that target the liver specifically - they are hepatotropic
Hepatitis viruses are lettered sequentially:
- Hepatitis A
- Hepatitis B
- Hepatitis C
- hepatitis D
- hep E
- non A/ nonB - old term used for viral hepatitis of unknown origin
While all hepatitis viruses cause hepatitis, the viruses themselves are quite differnet. The severity of their symptoms can vary in frequency and severity
Acute Hepatitis -symptoms
Frequency nad severity varies with virus
Mechanism is the same: immune-mediated damage to infected hepatocytes
Less specific sx—> more specific sx
Fever fatigue malaise nausea vomiting—> abdominal pain—> right upper quadrant abdominal pain—> hepatomegaly—> jaundice (icteric phase) with dark urine, pale stools, puritus (itchy skin), sclera icterus
Fulminant hepatitis- massive hepatic necrosis leading to death a rare outcome
- HEV causes this most commonly, followed by HAV and less frequently by HBV and HCV
NB hep A, B and C all cause an acute illness characterized by nausea, malaise, jaundice. Symptoms dont distinguish these viruses nor do they tell you that the hepatitis is due to a virus infection eg alcoholic cirrhosis is very common
Jaundice
Yellow discoloration of the skin, sclera, and mucus membranes
Sclera icterus (white of the eyes are yellow)
Due to systemic retention of pigmented bilirubin in tissues
Puriritus-itchy skin
You need to know about bilirubin because you can measure it - an important lab test
Bilirubin - breakdown product of hemoglobin
Conjugated = direct
Unconjugated = indirect
Total bilirubin = direct + indirect
Bilirubin not soluble; binds to albumin aand is transported to the liver
Conjugation occurs in liver, improves solubility
Erythrocytes are destroyed by macrophages in the spleen and bone marrow releasing hemoglobin which is degraded to heme; the globin is metabolized to its constituent amino acids while heme is converted into unconjugated bilirubin in macrophages of the spleen and bone marrow, bound to plasma albumin and transported to the liver
In the liver it is conjugated with glucuronic acid making it water soluble for excretion in the bile
Conjugated is most hepatic causes
Also hemolytic anemia, EHEC, malaria etc
Bilirubin metabolism and elimination
Jaundice can result from increased production, decreased excretion or both
Pre hepatic causes (mostly unconjugated bilirubin, indirect)
- increased bilirubin production (hemolytic anemia’s)
- reduced hepatocellular uptake (drugs interferences with transport systems)
- impaired conjugation (diffuse hepatocellular disease, hepatitis)
Post hepatic causes
(Mostly conjugated bilirubin, direct)
Decreased hepatocellular excretion - Dublin Johnson syndrome
Impaired bile flow
- biliary obstruction
More than one mechanism can operate to produce jaundice
Normally unconjugated bilirubin contributes more to the total serum bilirubin than the conjugated form since the later is produced n the liver and secreted into the bile
In addition to impaired bilirubin metabolism, death of hepatocytes releases various enzymes
Serum level of these enzymes (called Liver Function Tests) reflects the severity of disease
Follow LFTs over time to monitor disease progress
- ALT (alanine aminotransferase): more specific for liver abnormalities than other enzyme tests, high ALT suggests viral rather than alcohol hepatitis
- AST (aspartate aminotransferase): less specific, since AST present in muscle and other tissues, this is a mitochondrial enzyme also present in heart, muscle, kidney and brain and so is less specific for liver disease, in many cases of liver inflammation the ALT and AST activities are elevated in a 1:1 ratio
- AP (alkaline phosphatase): again less specific, but is indicative of bile cut injury, liver and non liver related disease elevated
- GT (gamma glutamate transpeptidase: often elevated in those who use alcohol or other liver toxic substances to excess
Chronic Hepatitis - symptoms
See image of cirrhosis end stage liver slide 13
If acute infection isnt cleared, patient may develop chronic hepatitis
Caused only by hep B and C with variable frequency
Can be
- asymptomatic (chronic p ersistent hepatitis)
- symptomatic (chronic active hepatitis; CAH)
Can lead to bad outcomes:
- cirrhosis (refers to the way the liver scars due to damage)
- hepatocellular carcinoma (malignant cancer, often induced by hepB or C but never A
Cirrhosis Liver
13 + 14
Bridging fibrosis in core biopsy
- fibrous bands connecting portal triads
As liver becomes cirrhosis it shrinks in size, externally it appears modular and is quite firm to the touch
- shrunken, micronodular, firm to touch
As it becomes cirrhosis, it becomes more difficult to pump blood through it—> elevated portal pressures
Liver cirrhosis- bridging fibrosis (bands of births scar tissue that connect the portal triads
Major cause of cirrhosis are chronic alcohol abuse, hep C, hep B
Cirrhosis
Rigid non compliant liver results in portal hypertension
Resulting symptoms just follow the anatomy —> increased venous pressure throughout leads to fluid transduction (ascites)
Increased pressure in the portal system: things back up - spleen enlarged, pressure in the venous system is increased and as a result fluid leaks out due to hydrostatic pressure giving rise to ASCITES (fluid in abdominal space)
Other outcomes ar hemorrhoids a nd esophageal varies - engorged veins in the lower esophagus, which if torn can lead to massive and life threatening blood loss since there is nothing to stop the bleeding
Classic presentation of cirrhosis
Patient who vomits copious amounts of bright red blood (suggests upper GI tract bleed and this is a medical emergency)
Cirrhosis also has metabolic consequences
Causes portal hypertension (—> varices, large spleen etc and ascites) and hepatic insufficiency (—> jaundice and hepatic encephalopathy)
Decreased clotting factors: coagulopathy
Decreased glycogen storage: hypoglycemia
Increased ammonia: hepatic encephalopathy (liver is not detoxifying blood insufficiently, you get high ammonia levels)
Hepatitis A virus
RNA picornavirus
- small
- RNA positive strand
- single serotype worldwide
- nonenveloped - quite stable outside the body
- acute disease and asymptomatic infection ONLY! No chronicity
- no cytopathic; symptoms result from immune-mediated destruction of virus infected cells, typical acute infection lifestyle
Spread by fecal oral route only and is acid stable; causes acute infections; infection confers life long immunity; there is a vaccine; infection is usuallly symptomatic, usually self-limited. Damage to the liver is from the immune response
Hep A virus pathogenesis
Enters bloodstream through oropharynx, replicates in GI tract then viremia spreads to liver
Virus produced and released into bile, and then shed into stool for about 10 days before symptoms appear
HAV replicates slowly in liver and is not cytopathic
Liver pathology due to immune response directed against virus-infected cells
Hep A virus: epidemiology
Affects 1.4 million worldwide annually
Common cause of acute haptitis
Enteric transmission
- spread person to person via fecal oral route
- acquired from contaminated food and water
- stable in fresh and salt water for long periods: shellfish common source- contaminated water; as filter feeders they concentrate the virus
Infection confers immunity
HAV outbreaks usually originate from a point source (daycare center, water supply, restaurant)
Spreads readily - infected people are contagious before they are symptomatic
Get HAV vaccine before traveling
HAV infection rates have decreased in the US by > 90% in recent years
Due to vaccine1!!
Since children are normally asymptomatic they play an important role in the sprea dof community outbreaks where virus is spread between close contacts
Now most outbreaks are associated with contaminated food
Mechanisms of food borne spread of HAV
1) clean food may be contained by a food handler who is incubating HAV
2) food may be contaminated at its source, eg shellfish harvested from waters contaminated with sewage or crops irrigated with contaminated water
Maternal-fetal Transmission and parenteral Transmission through blood transfusions are NOT major risk factors for HAV transmission (but HBV and HCV are)
Recent HAV outbreaks
Frozen strawberries in Virginia
Frozen scallops from the Philippines—> HAV outbreaks in several stages including sushi chain
Hep A virus; clinical sx
Acute self-limited- no chronic infection, no association with cancer; > 80% adults symptomatic
Symptoms occur abruptly 15-50 days post exposure, intensify for 4 - 6 days before icteric (jaundice phase)
- incubation is around 1 month and a duration of around 1 month
Infection usually asymptomatic in children
Hepatomegaly in 80%
Jaundice 70% adults, 15% children
Less common = splenomegaly, rash
Fulminant hepatitis rare 1 - 3 per 100
Hep A virus Diagnosis
Clinical symptoms/signs, their timing and identification of aknown infected source
Lab findings:
- increase in LFTs/bilirubin
Detect: serum HAV igM
- enzyme immunoassay
- 100% with acute HAV
- remain + for 3 - 6 months
IgG antibodies
- early in convalescence
- prior exposure to HAV (or vaccine)
- remain detectable for decades, 85% of individuals who are infected with HAV have a full clinical and biochemical recovery within 3 months, and all by 6
IgM is gold standard for diagnosing acute infection
HAV Treatment/control
Treatment: supportive since HAV is self limited
Full recovery within 3 months most common
Maintenance of sanitary conditions
- handwashing, cooked foods, avoid impure water
HAV vaccine
- two inactivated HAV vaccines available
- indications: travel, chronic liver disease
- recommended for children as routine immunization
HBV
Genome covered by the core antigen (HBcAg) which is surrounded by a lipid envelope and the surface Ag (HBsAg)
- HBsAg can assemble into subviral particles, not infectious but more common than virus in the blood of infected people
Another viral protein, called E antigen (HbeAg) is secreted from infected cells and can be detected in patient sera
HBsAg forms the basis of the vaccine that you have received
HBV has a partially dsDNA genome
- makes new DNA from viral RNA by using reverse transcriptase
HBV characteristics? Enveloped? Genome?
Dane particle?
HBV enveloped (spared by body fluids) with a partially double stranded DNA genome
Has a rather bizarre replication strategy in that it has a reverse transcriptase (RT) but not an integrase
Some drugs that work against HIV1 RT protein also work against the HBV RT protein, such as lumivudine, an NRTI
Viral DNA covered by core antigen HBcAg which in turn is covered by a lipid membrane from which protrudes the viral surface Ag (HBsAg) which can self assemble to form virus-like particles that can be found in the plasma of infected people—> forms the basis of recombinant subunit HBsAg vaccine
Subviral particles are much more common in the serum of patients that the real virus = DANE PARTICLE
HBV: what limits the effectiveness of antibodies
Presence of high levels of subviral particles since Ab bind to subviral particles and are soaked up
HBV epidemiology
About 400 million chornically infected worldwide
Between .7 - 1.4 mill chronically infected in US
Parenteral transmission
- IV drug use
- sexual transmission
- health care workers at risk
**major routes of infection are IV drug use and sexual transmission
HBV vaccine has decreased transmission
Geographic Distribution of Chronic HBV infection
Why are rates of HBV infection so high?
So high because chronic asymptomatic infections, especially in children
In highly endemic areas, hepB is most commonly spread from mother to child at birth (perinatal Transmission) or through horizontal transmission (exposure to infected blood), especially from an infected child to an uninfected child during the first 5 years of life
Development of chronic infection is very common in infants infected from their mothers or before the age of 5 years
HBV in the adult: natural history
Most ppl infected with HBV (75%) will not even know they were infected - they are asymptomatic and the virus is cleared
What makes HBV different from HAV is that sometimes the immune response does not clear infection; these people now become chronically infected, and usually remain so for the rest of their lives
Chronically asymptomatic - may have flare ups but are generally asymptomatic
Changes of progressing from acute to chronic HBV is primarily determined by the agent at infection
- younger you are, the more likely your immune response will be modest - clear infection and asymptomatic
90% perinatal acquired HBV progress to chronic disease, then 29-50% for HBV between age 1 - 5 years, 5 - 10% for adult acquired HBV infections
- chances of sympatomatic infx increase with time
2 bad outcomes of chronic infection are progressive cirrhosis —> liver failure and hepatocellular carcinoma
- coinfection with HIV, hep C virus, and superinfection with hep D virus can lead to accelerated disease progression
HBV clinical manifestations
Acute
- 70% subclinical = unlike hep A
- longer incubation period (several months) than hepA
- symptoms improve after 1 - 3 mo
Chronic HBV
- many pt asympatomatic for years
- fatigue most common symptom
- hepatomegaly early in course
- persistence depends on age at infx
- may be detected by observing increased LFTs in an asymptomatic person
- HBV is major cause of hepatocellular carcinoma
HBV and hepatocellular carcinoma
- chronic HBV infx increases risk of HCC by > 100 x
- 80% of all HCC attributable to HBV
- HCC one of the three most common causes of cancer mortality in the world
- HBV may induce HCC indirectly by promoting continued liver repair and cell growth in response to tissue damage
- integration and expression of some viral proteins may also promote tumor development directly by juxtaposing viral promoters next to cellular growth controlling genes (HBV can insert into the chromosome)
How do you tell if a patient is HBV infected? HBV serologies- what can you measure and what they mean
HBsAg - HBV surface antigen 9part of virus), if positive, patient is acutely or chronically infected
HBeAg - presence of E Ag (another viral protein) is indicative of high levels of infectious virus
Anti-HBsAg IgG - if positive then either vaccinated, infected in the past, or chronically infected if HBsAg also positive
Anti-HBCAg - IgG means that the patient has been infected in the past becuase HBcAg is NOT part of the vaccine; IgM means acute infection
Anti-HBcAg IgM - antigen B core antigen Ig M - detecting IgM that recognizes the core antigen means that the patient is acutely infected with IgM - positive IgM—> acute infection (doesnt predict whether the pt will become chronically infected)
HBV diagnosis - acute infection serology
32/59
HBsAg comes up first, and can be detected as early as 1 - 2 weeks and as late as 11 or 12 weeks after exposure to HBV
In persons who recover HBsAg is no longer detectable in serum after an avg period of about 3 months
HbeAg is generally detectable in patients with acute infection, in serum correlates with higher titers of HBV and greater infectivity
**diagnosis of acute HBV infx can be made on the basis of detection of IgM class Ab to hep B core antigens (IgM anti HBc) in serum
IgG anti-HBc persists indefinitely as a marker of past infection, presence of antiHBs IgG following acute infection is indicative of recovery and immunity from reinfection
BUT antiHBsAg by itself could mean vaccine
HBV diagnosis - chronic infx serology
In chronic infx, HBsAg is detected, but. Ab to HBsAg are often negative due to immune tolerance
Both HBsAg and IgG anti-HBc remain persistently detectable, for life
Presence of HBsAg for 6 mo or more —> chronic infection
In addition, a negative test for IgM anti-HBc together with a positive test for HBsAg in a single serum specimen usually indicates that an individual has chronic HBV infection
HBV treatment
No treatment for acute
Alpha interferon for chronic infx (PEG)
- suppress HBV replication
- activates monocytes and macrophages
- induces antiviral state in uninfected cells
- younger pt; no HIV; HCV+; certain HBV genotypes
- significant side effects; flu like Sxs common; psychiatric side effects
Replication blockers for chronic infx
- HBV has a reverse transcriptase enzyme
- lamivudine (nucleoside analog)
- adenovirus (nucleoside analog)
- drug resistance may arise
- children, pregnant women; guidelines complicated
HBV: prevention/control
HBV vaccine
- subunit vaccine based on HBsAg
- produced in yeast engineered to express HBsAg
- 3 doses of vaccine required, injected IM
- oversall seroconversion rate ~95%
- response = HBV surface Ab
- highly effective
HCV
Flavivirus
Positive strand RNA genome; lipid envelope with E1 and E2 glycoproteins protruding from its surface, these proteins are responsible for binding virus to the surface of hepatocytes via specific receptors and for mediating membrane fusion that allows virus into cells
6 genotypes, many subtypes and isolates based on nucleotide diversity—> implication for therapy
Viral polymerase is error prone and virus replicates at high levels—> genetic diversity and enable virus to evolve resistance to cellular immune response
Parenteral Transmission
Does not integrate (unlike hepB)
HCV epidemiology
What type of transmission
What is it the leading cause of
Genotypes
3.2 mill infected
85% of new infections become chronic - much more than HBV
HCV leading cause of
- chronic liver disease
- cirrhosis
- liver cancer
- liver transplantation
Parenteral transmission (like HBV)
- transfusion of blood products prior to 1992
- IV drug use; sexual transmission not as frequent as with HBV, less efficient sexual transmission
Six major HCV genotypes - makes a difference for treatment
- type 1 > 2> 3
Hep C testing for baby boomers
3% of cohort are HCV + and most dont know they are infected
Males 2x as likely to be infected as females
HCV Clinical manifestations
Symptoms of acute HCV rare
- malaise nausea, vomiting, abdominal pain
- jaundice in < 10%
- fulminant hepatitis following acute infection is rare
Symptoms of chronic HCV non specific
- fatigue
- intermittent nausea
- vague diffuse or RUQ abdominal pain
- myalgia, arthralgias
Extrahepatic manifestations
- immune complexes - glomerulonephritis, vasculitis
HCV natural history
Much higher rate of chronic infection than HBV
85% of ppl infected with HCV develop chronic infection, only 15% clear the virus
- the fact that HCV establishes a chronic, persistent infection so efficiently means that the virus must avoid and or subvert the immune system
- fact that virus mutates so quickly means it can get ahead of immune response
- HCV proteins play roles in subverting interferon response
Chronic infx increases risk for development of HCC—> cirrhosis and liver failure
Case presentation for HCV
IVDA risk factor for HBV, HCV, HIV (IV drug abuse)
Jaundice and elevated LFTs (HAV, HBV, HCV)
IGG positive for HAV (had hav vaccine or HAV in past)
IgG positive for HBV surface antigen but negative for core antigen (has HBV vaccine) and was HCV Ab positive (either had HCV or has had it in the past).. HCV RNA was high (HCV now)
Wait for pt to clear the infection on his own because of major side effects
HCV lab diagnosis
HCV antibody (do this for screening)
- enzyme immunoassay
- contains core and non structural proteins
- detect Ab within 4 - 10 weeks of infection
- false (-): immunocompromised pt
HCV viral load (use to monitor treatment)
- based on PCR techniques
- quantitative: predict response, monitor
- qualitative: detects as low as 100 copies/mL
- virus load does not predict disease progression
HCV Genotype
- done by sequencing; has implications for Tx
HCV treatment revolution
Old standard of care vs new standard of care
Old standard of care was combo therapy with Peggy lasted (PEG) interferon (IFN) and ribaviron, nucleoside analogue that interferes with HCV nucleic acid synthesis
- significant side effects —> mood disorders, rage, suicidality, insomnia, fatigue, depression, headaches, mania, fever flu-like symptoms
Genotype 1 cure rate (1yr) - 40-50% but.higher for HCV 2, 3, 4 (6 mo)
New standard HCV treatment : drugs that target viral enzymes
Recommended for all pt with chronic HCV infx except those with short life expectancies due to comorbidities conditions
Sample drug regimens; treat only 12 weeks, response rates > 90%
Treatment Hx of pt (=/- cirrhosis, drug resistance, HCV genotype can impact choice)
HCV antivirals are highly effective and IFN treatment is becoming a thing of the past
Treat with combos of the drugs for only 12 weeks without interferon basically cures!! Vast majority of SVRs sustained for atleast 5 yrs so HCV can be cured!
Hep D virus
Delta agent
Small RNA genome that produces only one protein
- single stranded circular RNA surrounded by delta antigen (coded for by the virus) which is surrounded by lipid membrane and HBV surface Ag
Requires HBV surface Ag to p a kale its genome - doesn’t have its own sAG
HDV can only establish an infection in people who are already HBV positive ***
Coinfection with HBV - usually recover
Superinfection with HDV- get HBV get better then get worse! - greatly increases risk of fulminant hepatitis and HCC
Hep D pathogenesis and immunity
Similar to HBV
- parenteral exposures most efficient
- Coinfection ina high acute coinfection with both HBV and HDV occurs, clinically indistinguishable from acute HBV infection and outcome is recovery
- Superinfection - HDV infects person who is already chronically infected with HBV, progression to chronic HDV infx usually results, HBV replication is suppressed by HDV, usually the dominant of the 2 viruses
Hep D epidemiology
5% of HBV infected individuals duality infected with HDV< higher rates outside US
IVDA major mode of transmission (as for HBV and HCV)
Hep D clinical disease
Once chronic HDV infx established—> rapid progression of liver disease
Cirrhosis in 15% within 1 - 2 yrs of disease onset
Chronic HDV increase risk of hepatocellular carcinoma
Clinical symptoms and signs of acute HDV infx are similar to those seen with other forms of acute viral hepatitis—> malaise fatigue anorexia, nausea, vomiting and abdominal pain
Jaundice and hepatomegaly identified on physical exam… HDV makes everything worse!
Hep D ELISA assays
Detect Ab and PCR to detect viral RNA
Hep D treatment and prevention
Nada
Hep E virus
Non enveloped RNA virus that is rare in US
Endemic in other parts of the world
Acute self limited viral hepatitis, doesnt lead to chronic infx
Mortality rates low but this is still higher than what is seen with HAV (with which it shares most in common with clinically)
Important: HEV infx in a pregnant woman carries with it a 20% mortality
HEV diagnosis
IgM detected 1 - 4 weeks after the onset of disease, whereas HEV igG can be detected 2 - 4 weeks after disease onset
HEV EPi
Highest incidence of HEV infection in Asia, Africa, Middle East and Central America
- transmitted from mother to newborn with substantial perinatal morbidity and mortality
- only sporadic cases in western countries and these have been linked to travel from endemic areas
HEV clinical disease
Self limited acute viral hepatitis, lasting 1 - 4 weeks, not progress to chronic disease
Incubation period is 15 - 60 days
Clinical symptoms and signs of acute
HEV infx are similar to those seen with other forms of acute viral hepatitis
May be asymptomatic or may cause hepatitis
- malaise, fatigue, anorexia, nausea, vomiting, abdominal pain
Fulminant hepatitis can occur more frequently in pregnancy (3rd trimester)
NO Treatment except supportive
45 yr old pt suspected of having hep Lab tests HBsAg - positive Anti-HAV IgG - positive AntiHAV IgM — negative Anti HBs IgG - negative AntiHBc IgM positive
This suggests he has a primary infection with HBV now and has had HAV in the past, could have had the HAV vaccine as well
Lab tests performed for a 22 yr old farmer who has not been feeling well for the past 3 months show high levels of aspartate transaminase, leukopenia, and decreased serum albumin
Most likely diagnosis is:
Hep A - elevated LFTs, decreased albumin which is made in the liver, lengthy time are all consistent with a hepatic process
How would you interpret the following serology markers for HBV?
+ HBsAg
+ IgG Anti-HBc
+ IgM Anti HBc
- HBs IgG
+ HBsAg - person is infected- doesnt tell you if the infection is acute or chronic
+ IgG Anti-HBc - by itself, means the person is currently infected or has cleared the infection
+ IgM Anti HBc- IgM positivity ALWAYS means acute infection- this trumps everything
- HBs IgG - IgM to core comes up first - then IgG to core, then IgG to HBsAg. In chronic infection don’t have IgG to HBsAg, if this were positive it would not change anything.. patient is acutely infected; IGG has not developed yet
Which of the following is least likely to result in symptoms during acute infection and which is most likely ot result in symptoms
Hep A B C D E
Hep A- maybe 70% in adults but much less in kids- most likely to cause symptoms
B- 25039% symptomatic
C- acute symptoms rare
D- cant cause acute infection on its own
E- probably more than 50% adults symptomatic
Acute: A > B> C
Chronic C> B> A (A doesnt cause chronic)