4. Not sexually transmitted well
What viruses can cause hepatitis?
Hep A-E, HSV, CMV, and EBV
What are the possible clinical presentations of viral hepatitis?
1. acute hep
2. fulminant hepatic failure
3. Chronic hep with complications including cirrhosis, liver failure, and possibly hepatocellular carcinoma
How do hep A, B, and E (rare in the US) typiclly present?
Hep A and E can only cause ACUTE hepatitis while Hep B can cause acute or chronic but is more likely to cause acute. Most cases of acute hepatitis resolve with the main complication of unresolved being fulminant liver failure
Note that mild forms of acute hepatitis tend to go unnoticed (subclinical)
Which hepatitis viruses can cause chronic hepatitis?
Hep C only causes chronic and again hep B can cause chronic but is more likely to cause acute. Hep D can only occur in the presence of a Hep B infection. The complications of chronic hepatitis include cirrhosis, and hepatocellular carcinoma
This is acute liver failure (only have 48 hrs!!)
B and E
How does acute hepatitis present?
Acute viral hepatitis follows a pattern of infection that involves three distinct phases:
The initial prodromal phase (preceding symptoms) involves non-specific and flu-like symptoms common to many acute viral infections. This includes fatigue, nausea, vomiting, poor appetite, joint pain, and headaches. Fever, when present, is most common in cases of hepatitis A and E.[ Late in this phase, people can experience liver-specific symptoms, including choluria (dark urine) and clay-colored stools.
Clinical jaundice (yellowing of the skin) and icterus (yellowing of the eyes) follow the prodrome after about 1–2 weeks and can last for up to 4 weeks. The non-specific symptoms seen in the prodromal typically resolve by this time, but people will develop an enlarged liver and right upper abdominal pain or discomfort. 10–20% of people will also experience an enlarged spleen, while some people will also experience a mild unintentional weight loss.
The recovery phase is characterized by resolution of the clinical symptoms of hepatitis with persistent elevations in liver lab values and potentially a persistently enlarged liver. All cases of hepatitis A and E are expected to fully resolve after 1–2 months. A majority of hepatitis B cases are also self-limited and will resolve in 3–4 months. Few cases of hepatitis C will resolve completely (aka theres no such thing as acute Hep C)
How will acute hepatitis look in labs?
-high ALT/ASTs (1000-5000 Iu/L)
-elevated bilirubin and prothrombin time
What is a normal bilirubin level?
A normal level is: Direct (also called conjugated) bilirubin: 0 to 0.3 mg/dL. Total bilirubin: 0.3 to 1.9 mg/dL
What is a normal INR?
In healthy people an INR of 1.1 or below is considered normal
In acute hepatitis, an INR approaching 3-4 suggests what?
progression to fulminant liver failure
What is fulminant liver failure?
The main features of acute liver failure are rapid-onset jaundice, weakness, and eventually changes in mental status that can begin as mild confusion but progress to coma
What is on the Ddx for acute hepatitis?
-Autoimmune liver disease
-Ischemic hepatitis (LEs may get up to 1000)
-Alcohol/drug induced, Tylenol overdose (LEs may get up to 500)
-Wilson disease (LEs up to 500)
What is Wilson Disease?
Wilson's disease is a genetic disorder in which copper builds up in the body. Symptoms are typically related to the brain and liver. Liver related symptoms include vomiting, weakness, fluid build up in the abdomen, swelling of the legs, yellowish skin, and itchiness. Brain related symptoms include tremors, muscle stiffness, trouble speaking, personality changes, anxiety, and seeing or hearing things that others do not
How is the diagnosis of Hep A made?
The diagnosis of acute HAV infection is confirmed during the acute or early convalescent phase of infection by the presence of IgM antibodies to HAV (IgM anti-HAV). IgM anti-HAV is generally present 5-10 days before the onset of symptoms and is no longer detectable in the vast majority of patients 6 months later. IgG anti-HAV, which also appears early in the course of infection, remains detectable for the lifetime of the individual and confers lifelong protection against infection. Commercial tests are available for the detection of IgM and total (IgM and IgG) anti-HAV in serum.
HAV RNA can be detected in the blood and stool of most persons during the acute phase of infection by using nucleic acid amplification methods, such as PCR, and nucleic acid sequencing has been used to determine the relatedness of HAV isolates. These methods, however, are available in only a limited number of research laboratories and are not used generally for diagnostic purposes.
When is Hep A infection most common?
In infected persons, HAV replicates in the liver, is excreted in bile, and is shed in the stool. Peak infectivity occurs during the 2-week period before onset of jaundice or elevation of liver enzymes, when the concentration of virus in stool is highest. The concentration of virus in stool declines after jaundice appears. Children and infants can shed HAV for longer periods than adults, up to several months after the onset of clinical illness. Chronic shedding of HAV in feces does not occur; however, shedding can occur in persons who have relapsing illness. Viremia occurs soon after infection and persists through the period of liver enzyme (alanine aminotransferase [ALT]) elevation.
What are the possible outcomes of acute hepatitis?
1. Spontaneous resolution (most common)- (Both Hep A and Hep E can rarely have a relapsing course with cholestasis) – 95% of Hepatitis B resolve
2. Progression to chronic infection (5% in HBV and ~80% in HCV) 0% chance of chronicity in Hep A or E
3. Fulminant liver failure (<1%)
Which types of acute hep infection are most likely to lead to fulminant liver failure?
All rare but HBV more common than HAV and HEV can only cause in pregnant women (in 3rd trimester most often)
Describe the genome of Hep A
Non-enveloped +strand RNA virus
How is Hep A contracted?
The virus is primarily spread when an uninfected (and unvaccinated) person ingests food or water that is contaminated with the faeces of an infected person. The disease is closely associated with unsafe water or food, inadequate sanitation and poor personal hygiene.
How does hep A cause liver injury?
CD8 T cells and NK cells lead to heaptic injury before clearance
What is the incubation period of Hep A?
T or F. HAV rarely causes acute liver failure
T. Only about 5% of times and 70% of those pts. recover
How does Hep A present?
Many cases have few or no symptoms, especially in the young. The time between infection and symptoms, in those who develop them, is between two and six weeks. When symptoms occur, they typically last eight weeks and may include nausea, vomiting, diarrhea, jaundice, fever, and abdominal pain. Around 10–15% of people experience a recurrence of symptoms during the six months after the initial infection. Acute liver failure may rarely occur, with this being more common in the elderly
What are some atypical presentations of Hep A?
-Extrahepatic manifestations occurring
What are the symptoms of cholestasis (i.e. from obstruction, metabolism errors, hepatitis)?
itchiness (pruritus). Pruritus is the primary symptom of cholestasis and is thought to be due to interactions of serum bile acids with opioidergic nerves. In fact, the opioid antagonist naltrexone is used to treat pruritus due to cholestasis.
jaundice. Jaundice is an uncommon occurrence in intrahepatic (metabolic) cholestasis, but is common in obstructive cholestasis.
pale stool. This symptom implies obstructive cholestasis.
What are some of the extrahepatic manifestations of hep A?
-arthralgia and evanescent rash (11%)
Transverse myelitis- a neurological condition in which the spinal cord is inflamed. The inflammation damages nerve fibers, and causes them to lose their myelin coating leading to decreased electrical conductivity in the central nervous system. Transverse implies that the inflammation extends across the entire width of the spinal cord. Partial transverse myelitis and partial myelitis are terms used to define inflammation of the spinal cord that affects part of the width of the spinal cord.
How does hep E present?
Mainly as a self-limited acute hepatitis with a low risk of acute liver failure occurring except in pregnant, immunocompromised, and elderly pts.
What is the key to Acute Hep A, B, and E diagnosis?
HAV: IgM and anti-HAV Ab
HEV: IgM and anti-HEV Ab
Acute HBV: IgM and anti-HB core Ab
What does a + IgG Ab mean?
indicates previous infection (either resolved or active chronic infection)
What does + Viral RNA or DNA mean?
:indicates active infection does not differentiae b/w acute vs chronic infection
How does fulminant hepatic failure present?
It is most likely to be caused by HBV or HEV in pregnant women (rarely HAV) and is predicted by the onset of altered mental status (aka hepatic enchepalopathy)
What causes the hepatic encephalopathy in fulminant liver failure?
Fulminant liver failure has a high mortality rate especially due to what?
brain herniation and infection
ow should fulminant liver failure be handled?
liver transplant within 48 hrs
What is the most common cause of acute liver failure In US?
is acetaminophen overdose
How is chronic viral hepatitis defined?
6+ mos. of infection (almost all caused by HCV or HBV)
How does chronic viral hepatitis present?
Most aymptomatic (most found incidentally during checkups)
There can be mildly elevated LEs (up to 200 at most usually) but they can be normal (does rule out chronic hepatitis)
liver failure and/or cancer occur after several years and extrahepatic manfestiations do occur
What is the progression of chronc HBV and HCV?
normal -> fibrosis -> cirrhosis -> HCC
This typically requires 20-30 yrs
What things can cause acceleration of the progression of chronic hepatitis to cirrhosis/HCC?
-obesity (fatty liver)
Where is HBV highest in the world?
Asia and India
–Asian Americans are 2.7 times more likely to develop hepatocellular carcinoma (HCC) and 2.4 times more likely to die from HCC than their white counterparts3
What groups of people should be routinely screened for HBV?
-Persons born in regions with high prevalence of HBV infection (HBsAg prevalence 2+%)= Asians
-All pregnant women and infants born to HBsAg+ women
-IV drug users
-donors of blood, plasma, organs, or semen and hemodiaylsis pts.
-HIV+, immunosuppressed, or those with increased ALT/AST of unknown cause
What are the blood tests for HBV?
Hep B e antigen and anti-hep B e Ab
anti HBcore Ab IgM and IgG (core antigen cannot be measured)
-HB surface antigen (HBsAg) (presence indicates that you HAVE HBV)
What is the most important test for chronic HBV?
Positive HBs Ag surface antigen (+= you have ACTIVE infection (acute or chronic)
What do positive Anti-HB Abs mean?
resolved infevction or prior exposure/vaccination
What does a positive HB core Ab mean?
Definite exposure (not seen in vaccination)
(IgM= acute; IgG= resolved or chronic infection)
What does a positive hep B e antigen and high DNA mean?
active replication and high risk of transmission
HBV Serology Chart
What are the phases of chronic HBV infection?
Describe the immune tolerant phase of chronic HBV
there is little hepatic inflammation despite a high serum level of HBV DNA and positive HBeAg. Disease stays in the liver to replicate but no liver disease and immune doesn’t recognize it
Describe the immune clearance phase of chronic HBV
there is hepatic inflammation and decrease in serum HBV DNA level and ultimately loss of HBeAg (still positive during this phase however). This phase is also known as HBeAg+ CHB. After 10-15 yrs this occurs. Lasts 5-6 yrs
Describe the inactive carrier state of chronic HBV infection
normal aminotransferases, low level of HBV Dna and negative HBeAg
Describe the reactivation state of chronic HBV infection
high levels of HBV DNA can be detected in serum along with hepatic inflammation (elevated LEs). Many patients remain HBeAg negative, but some patients may revert to HBeAg positive. This phase is also known as HBeAg- CHB.
Not all patients go through all the four phases. The immune clearance phase is most common in young Asian patients with perinatally acquired HBV infection. Some patients remain in the inactive carrier phase with no evidence of reactivation, these patients have better prognosis than those who develop reactivation. The immune clearance phase and reactivation phase may be prolonged with recurrent exacerbations of hepatitis and fluctuations in serum HBV DNA levels.
When do you tx chronic HBV?
1. When there is evidence of liver injury (high AKT- i.e. usually immune clearance and reactivation phases only)
2. When a liver biopsy shows fibrosis
What are the goals of HBV tx?
-cannot be cured in most pts. (5-10% at most- 'cured' means loss of HB surface antigen +)
-decrease HBV replication to lower DNA which minimizes liver injury and prevents progression
-decrease risk of HCC
What drugs are available to tx HBV?
-Entecavir and Tenofovir (1x PO that are taken indefinitely). target replication and viral resistance can occur!
SQ Pegylated Interferon Alfa 2a for a finite period to modulate the immune system
T or F. Pegylated Interferon Alfa 2a tx is contraindicated in cirrhosis pts.
Describe Hep D
Not a complete virus and requires Hep B surface antigen presence to infect (seen ONLY in HBV pts)
Can cause either a super infections or co-infection
Notes about Hep D co-infection with chronic HBV
It increases both the severity of HBV and the risk of cirrhosis
How is the diagnosis of HDV infection made?
-delta Ab or RNA (all pts. MUST have a + Hep B surface antigen to be diagnosed)
What is the most common chronic viral hepatitis in the US?
Most common reasons for liver transplant in order: NASH, Hep C, alcohol
T or F. HCV is Nearly 4 Times as Prevalent as HIV and HBV
HCV also currently causes more deaths than HIV/yr
T. Most are undiagnosed because it doesnt present with many symptoms
•The number of patients with HCC began to rise steeply after 1990 and is projected to peak in 2019.
•The aging baby boomer population (aged 60 years and older) has been found to be the age group most affected with cirrhosis and its complications (decompensated cirrhosis and HCC).
The prevalence of HCV in HCC patients ranges from 20% to 90%, and the absolute risk of HCC in HCV-related cirrhosis ranges from 1% to 7%.
___% of patients infected with HCV will develop a chronic infection
–~65% of these patients are expected to develop progressive chronic liver disease
–40% risk of cirrhosis and HCC may occur in the setting of F3 fibrosis
Who should get screened for HCV?
-1 time screenng for adults born between 1945-1965
-past or current IVD use or intranasal drug use
-long-term kidney dialysis
-recipients of blood transfusion or organ transplant before 1992, or blood from someone who later tested positive for HCV
-health care work exposed to HCV-blood
-HIV+, unexplained chronic liver disease
-children born to HCV-infected mothers
-receipt of an unsterile/unregulated tattoo
How is HCV tested for?
Hep C Ab by enzyme immunoassay for screening for past or present infection
-PCR for HCV RNA for confirmation of positive EIA, and for medical evaulation and management
Prevalence of genotype is different in various geographic area indicating the pattern of spread and may be population migration .
Most common in developed countries? South Africa?
Middle East and north Africa? IVDU?
Asia? Americas and West Europe?
South Africa: 5
Middle East: 4
Americas + Europe: 1
Tx options for HCV
Most common is Sofosbuvir combo
Principles of All Oral Regimens for HCV
•Combine drugs from different classes
–Target multiple targets to increase efficacy
–Decrease risk of viral resistance
•If done properly
–Near universal efficacy (close to 100% cure rate)
–Shortened duration of therapy
–Adverse events have minimal impact on patient’s quality of life
–Can treat all genotype with single regimen (reducing complexity of treatment)
T or F. HCV is curable with treatment (unlike HBV or HIV)
T. Will cure even with cirrhosis but the cirrhosis will not get better probably
What vaccines are available for HAV and HBV?
HAV- 2 doses
HBV- 3 doses
TWinrix is a combo vaccine (all pts. with chronic liver disease should get vaccinated)
What vaccines are available for HEV?
Not available in the US. Two outside the US:
1) Recombinant capsid antigen rHEV
2) HEV 239
What vaccines are available for HCV?
1. Contains Envelop protein E1 and E2
2. Designed to induce CD4/CD8 cell response against Non structural protein of HCV
Clinical Trials underway
T or F. All HIV pts should be tested for HBV and HCV
-Natural history of HBV and HCV is worse and chance of spontaneous clearance is low
-HCV is now leading cause of death in HIV patients
How should a pt. that is both HIV and HBV positive be tx?
Tenofovir (Truvada*, Atripla*)
None of HCV drugs has anti HIV activity
Descibe the relationship between HBV adn HCV and HCC
•HCV causes HCC only with cirrhosis
HBV can cause HCC even without cirrhosis
•Cancer screening by Ultrasound is recommended in all patients with Cirrhosis from HBV and HCV every 6mos (some non cirrhotic HBV patients also require s creening )
What are the indications for a lvier transplant in viral hepatitis?
1. Cirrhosis with liver failure (HCV and HBV, HDV)
2. Hepatocellular carcinoma (HCV and HBV, HDV)
3. Fulminant hepatic failure (more in HBV>HEV>HAV)
What are some extrahepatic manifestations of chronic (B/C) Viral hepatitis?
•Porphyria cutanea tarda
•Mixed cryoglobulinemia (vasculitis,neuropathy)
-Extra hepatic manifestations may correlate with Viral RNA/DNA levels
-Treatment is indicated and can be successful if Viral replication can be reduced
What is Porphyria cutanea tarda?
Porphyria cutanea tarda (commonly referred to as PCT) is recognized as the most prevalent subtype of porphyritic diseases.
The disease is characterized by onycholysis and blistering of the skin in areas that receive higher levels of exposure to sunlight. The primary cause of this disorder is a deficiency of uroporphyrinogen decarboxylase (UROD), a cytosolic enzyme that is a step in the enzymatic pathway that leads to the synthesis of heme. While a deficiency in this enzyme is the direct cause leading to this disorder, there are a number of both genetic and environmental risk factors that are associated with PCT.
Typically, patients who are ultimately diagnosed with PCT first seek treatment following the development of photosensitivities in the form of blisters and erosions on commonly exposed areas of the skin. This is usually observed in the face, hands, forearms, and lower legs. It heals slowly and with scarring. Though blisters are the most common skin manifestations of PCT, other skin manifestations like hyperpigmentation (as if they are getting a tan) and hypertrichosis (mainly on top of the cheeks) also occur.
What are some other viruses that can cause viral hepatitis?
- Cytomegalo virus (CMV)
-Epstein Barr - Mononucleosis
-ALT and AST range 300-600 IU/L
-Self limiting in most patients
-Serious infection in immunocompromised patients
EBV in viral hepatitis
• Ubiquitous worldwide (90-95% seroprevalence)
• Self-limited elevation in transaminases with infectious
• Severe hepatitis and ALF has been reported
• Treatment is supportive
• Corticosteroids may be trialed in severe hepatitis
• Acyclovir may have role
Herpes Simplex Virus (HSV) hepatitis
• Rare cause of ALF (4/1033, 0.3%)
• Series of 137 patients with HSV hepatitis: 80% developed ALF; 24% were immunocompetent
• Acyclovir reduced risk of death (OR 0.14)
• Empiric treatment with acyclovir 5-10mg/kg q8h
CMV in Immunocompotent pts.
• Self-limited subclinical elevation in transaminases
• Diagnosis: CMV IgM+, 4-fold increase in IgG, +QNAT
• Reactivation common in ICU (up to 36% of patients)1
• Rare association with PVT and granulomatous hepatitis
• No data to support treatment unless tissue invasive disease
How does CMV related hepatitis present in Immunocompromised Patients?
-Fever , diarrhea (involvement of GI tract)
-Acute increase in ALT and AST
CMV Hepatitis in Immunocompromised Pts.
Diangosis: CMV DNA or tissue biopsy – Liver or GI tract
-Prophylaxis is recommended with Valcyclovir (organ transplant recipients)
Inclusion bodies picture in CMV hepatitis
T or F. All immunocompromised patients should be tested for HBV (i.e. before transplant, etc.)
T. Natural history likely to be worse and chance of spontaneous clearance is low in reactivated HBV in immunocompromised pts.
nAcute presentation likely due to reactivation of “inactive infection”
Prophylaxis (Lamivudine or Entecavir etc.) is indicated in all patients receiving chemotherapy if they are HBV surface antigen positive