Viral Hepatitis Flashcards
Hepatits C and Pregnancy
Hepatitis C is likely to become a significant public health problem in the UK in the next decade. It is thought around 200,000 people are chronically infected with the virus. At risk groups include intravenous drug users and patients who received a blood transfusion prior to 1991 (e.g. haemophiliacs).
Women in the UK are not currently screen for hepatitis C in the antenatal period.
Transmission risk
the vertical transmission rate from mother to child is about 6%. The risk is higher if there is a high viral load or coexistent HIV
Hepatitis C and Pregnancy - Mx
Management
there are no definitive guidelines for the management of women with hepatitis C in pregnancy, the following is based on expert reviews
standard drug therapy of pegylated interferon-alfa (IFN-) and ribavirin cannot be used in pregnancy due to concerns about teratogenicity
the evidence base surrounding the use of caesarean section vs vaginal delivery is inconclusive, but it is not currently routine practice to offer a caesarean section. Cochrane state: ‘Currently there is no evidence from randomised controlled trials upon which to base any practice recommendations regarding planned caesarean section versus vaginal delivery for preventing mother to infant Hepatitis C Virus transmission’
exposure to maternal blood e.g. due to perineal tears significantly increases the risk of passing on the virus
breastfeeding is not contraindicated in mothers with hepatitis C
Hep C - Reducing Vertical Transmission - Example Question
A 29-year-old woman who is a former intravenous drug user is seen in the hepatology clinic. She is 12 weeks pregnant and has been referred as she is known to have chronic hepatitis C. Twelve months ago she was treated with pegylated interferon-alpha, ribavirin and a a protease inhibitor which failed to result in her clearing the hepatitis C virus.
What is the most appropriate way, if any, to reduce the risk of vertical transmission?
Caesarean section Further course of antiviral therapy during pregnancy Advise against breastfeeding Antiviral therapy for the neonate for the first 4 weeks > None of the above interventions is recommended
Hepatitis E
Hepatitis E
Overview
RNA hepevirus
spread by the faecal-oral route
incubation period: 3-8 weeks
common in Central and South-East Asia, North and West Africa, and in Mexico
causes a similar disease to hepatitis A, but carries a significant mortality (about 20%) during pregnancy especially as women approach 3rd trimester
does not cause chronic disease or an increased risk of hepatocellular cancer
a vaccine is currently in development*, but is not yet in widespread use
*New England Journal of Medicine 356:895, 2007
Severe Hepatitis in pregnant woman - Think Hep E
Hepatitis E and Pregnancy - Example Question
A 26-year-old pregnant women is seen on the acute medical unit. She is 24 weeks pregnant with her first child and has been admitted by her GP after feeling generally unwell with ‘flu like symptoms and developing jaundiced sclera. Her stay in Bangladesh lasted 2 weeks during which time she visited family. Prior to travelling she was vaccinated against hepatitis A.
On examination her sclera are visibly jaundiced. Blood pressure is 108/60 mmHg, temperature 38.1ºC and pulse 96/min. She is slightly tender in the right upper quadrant of the abdomen. Bloods show the following:
Bilirubin 72µmol/l ALP 252 u/l ALT 342 u/l γGT 286 u/l Albumin 38 g/l CRP 154 mg/l
What is the most likely diagnosis?
Dengue fever > Hepatitis E Hepatitis A Intrahepatic cholestasis of pregnancy Acute fatty liver
Hepatitis E is more likely to cause severe disease in pregnant women. Hepatitis A is unlikely given her previous immunisation against this. There are no other features to support the remaining three distractors.
Hepatitis B
Hepatitis B is a double-stranded DNA hepadnavirus and is spread through exposure to infected blood or body fluids, including vertical transmission from mother to child. The incubation period is 6-20 weeks.
The features of hepatitis B include fever, jaundice and elevated liver transaminases.
Hepatitis B - Complications
Complications of hepatitis B infection chronic hepatitis (5-10%) fulminant liver failure (1%) hepatocellular carcinoma glomerulonephritis polyarteritis nodosa cryoglobulinaemia
Hepatitis B - Immunisation
Immunisation against hepatitis B (please see the Greenbook link for more details)
contains HBsAg adsorbed onto aluminium hydroxide adjuvant and is prepared from yeast cells using recombinant DNA technology
most schedules give 3 doses of the vaccine with a recommendation for a one-off booster 5 years following the initial primary vaccination
at risk groups who should be vaccinated include: healthcare workers, intravenous drug users, sex workers, close family contacts of an individual with hepatitis B, individuals receiving blood transfusions regularly, chronic kidney disease patients who may soon require renal replacement therapy, prisoners, chronic liver disease patients
around 10-15% of adults fail to respond or respond poorly to 3 doses of the vaccine. Risk factors include age over 40 years, obesity, smoking, alcohol excess and immunosuppression
testing for anti-HBs is only recommended for those at risk of occupational exposure (i.e. Healthcare workers) and patients with chronic kidney disease. In these patients anti-HBs levels should be checked 1-4 months after primary immunisation
the table below shows how to interpret anti-HBs levels:
Anti-HBs level (mIU/ml) and Response
> 100:
Indicates adequate response, no further testing required. Should still receive booster at 5 years
10 - 100
Suboptimal response - one additional vaccine dose should be given. If immunocompetent no further testing is required
< 10
Non-responder. Test for current or past infection. Give further vaccine course (i.e. 3 doses again) with testing following. If still fails to respond then HBIG would be required for protection if exposed to the virus
Hepatitis B - Mx
Management of hepatitis B
pegylated interferon-alpha used to be the only treatment available. It reduces viral replication in up to 30% of chronic carriers. A better response is predicted by being female, < 50 years old, low HBV DNA levels, non-Asian, HIV negative, high degree of inflammation on liver biopsy
whilst NICE still advocate the use of pegylated interferon firstl-line other antiviral medications are increasingly used with an aim to suppress viral replication (not in a dissimilar way to treating HIV patients)
examples include tenofovir and entecavir
First Line = Peginterferon alfa-2a.
In patients who do not undergo HBeAg seroconversion or who relapse, tenofovir disoproxil is second line. Entecavir is an alternative second line when patients are unable to tolerate tenofovir disoproxil.
Hepatitis B Mx - Example Question
A 35-year-old ex intravenous drug user has been diagnosed with has HBe-Ag positive Hepatitis B. Her investigation results are shown below:
HBV DNA 2100 IU/ml
ALT 60 IU/L
ALT last checked 3 months ago and found to be ALT 60 IU/L.
What is the recommended first line treatment for this patient?
Tenofovir disoproxil Entecavir > Peginterferon alfa-2a Telbivudine Sofosbuvir
The correct answer here is Peginterferon alfa-2a.
In patients who do not undergo HBeAg seroconversion or who relapse, tenofovir disoproxil is second line. Entecavir is an alternative second line when patients are unable to tolerate tenofovir disoproxil. Telbivudine is no longer recommended for the treatment of chronic Hepatitis B. Sofosbuvir is used for treating hepatitis C.
Hepatitis C
Hepatitis C is likely to become a significant public health problem in the UK in the next decade. It is thought around 200,000 people are chronically infected with the virus. At risk groups include intravenous drug users and patients who received a blood transfusion prior to 1991 (e.g. haemophiliacs).
Pathophysiology
hepatitis C is a RNA flavivirus
incubation period: 6-9 weeks
Features
after exposure to the hepatitis C virus less than 20% of patients develop an acute hepatitis
Complications
chronic infection (80-85%) - only 15-20% of patients will clear the virus after an acute infection and hence the majority will develop chronic hepatitis C
(unlike in Hep B where only 5-15% develop chronic infection)
cirrhosis (20-30% of those with chronic disease)
hepatocellular cancer
cryoglobulinaemia
porphyria cutanea tarda (PCT): it is increasingly recognised that PCT may develop in patients with hepatitis C, especially if there are other factors such as alcohol abuse
Hepatitis C - Transmission
Transmission
the risk of transmission during a needle stick injury is about 2%
the vertical transmission rate from mother to child is about 6%. The risk is higher if there is coexistent HIV
breast feeding is not contraindicated in mothers with hepatitis C
the risk of transmitting the virus during sexual intercourse is probably less than 5%
Hepatitis C - Fx and Cx
Features
after exposure to the hepatitis C virus less than 20% of patients develop an acute hepatitis
Complications
chronic infection (80-85%) - only 15-20% of patients will clear the virus after an acute infection and hence the majority will develop chronic hepatitis C
cirrhosis (20-30% of those with chronic disease)
hepatocellular cancer
cryoglobulinaemia
porphyria cutanea tarda (PCT): it is increasingly recognised that PCT may develop in patients with hepatitis C, especially if there are other factors such as alcohol abuse
Hepatitis C - Mx and Cx of Treatment
Management of chronic infection
treatment depends on genotype
currently a combination of pegylated interferon-alpha, ribavirin and a a protease inhibitor (e.g. boceprevir, simeprevir and telaprevir) is used
cure rates are now approaching 90%, including for some strains which have been previously difficult to treat
the aim of treatment is sustained virological response (SVR), defined as undetectable
serum HCV RNA six months after the end of therapy
Complications of treatment
ribavirin - side-effects: haemolytic anaemia, cough. Women should not become pregnant within 6 months of stopping ribavirin as it is teratogenic
interferon alpha - side-effects: flu-like symptoms, depression, fatigue, leukopenia, thrombocytopenia
Hepatitis C - Mx - Example Question
A 42-year-old man with genotype 4 hepatitis C and early hepatic fibrosis on liver biopsy comes to the clinic to discuss the preferred options for anti-viral therapy. His LFTs have been stable over the past few months and results are shown below;
Bilirubin 11 µmol/l ALP 141 u/l ALT 82 u/l γGT 89 u/l Albumin 37 g/l
Which of the following is the most appropriate intervention?
> Simeprevir, interferon alpha and ribavirin Interferon alpha and lamivudine Interferon alpha and ribavirin Ribavirin and lamivudine Grazoprevir and lamivudine
Simeprevir is a NS3/4A hepatitis C virus (HCV) protease inhibitor, a cornerstone of modern management for hepatitis C. It is recommended by NICE for genotypes 1 and 4 in combination with interferon alpha and ribavirin.
Lamivudine and interferon alpha in combination were a combination treatment used historically for hepatitis B. Interferon alpha and ribavirin. Dual therapy with interferon alpha and ribavirin was historically used for hepatitis C, but this has now been replaced by the targeted newer agents. Ribavirin and lamivudine are not used in combination for hepatitis C. Grazoprevir is an NS3/4a protease inhibitor used in hepatitis C treatment, it is not usually used in combination with lamivudine however.
https://www.evidence.nhs.uk/formulary/bnf/current/5-infections/53-antiviral-drugs/533-viral-hepatitis/5332-chronic-hepatitis-c/simeprevir
Hepatitis C Mx: Genotypes 1 and 4
Simeprevir is a NS3/4A hepatitis C virus (HCV) protease inhibitor, a cornerstone of modern management for hepatitis C. It is recommended by NICE for genotypes 1 and 4 in combination with interferon alpha and ribavirin.
Hepatitis D
Hepatitis D
Hepatitis D is a single stranded RNA virus that is transmitted parenterally. It is an incomplete RNA virus that requires hepatitis B surface antigen to complete its replication and transmission cycle.
It is transmitted in a similar fashion to hepatitis B (exchange of bodily fluids) and patients may be infected with hepatitis B and hepatitis D at the same time.
Hepatitis D terminology:
Co-infection: Hepatitis B and Hepatitis D infection at the same time.
Superinfection: A hepatitis B surface antigen positive patient subsequently develops a hepatitis D infection.
Superinfection is associated with high risk of fulminant hepatitis, chronic hepatitis status and cirrhosis.
Diagnosis is made via reverse polymerase chain reaction of hepatitis D RNA. Interferon is currently used as treatment, but with a poor evidence base.
Hepatitis B Decompensation - Example Question
A 57-year-old male with chronic hepatitis B infection presents to the Emergency Department with increasing confusion. His wife states that his specialist has not started him on antivirals yet. He was diagnosed six months ago. His past medical history includes tuberculosis that has been successfully treated 10 years ago.
His wife stated also that he slept more than usual in the last week and he was more lethargic. On examination the patient was confused, disoriented with a yellowish discoloration of his eyes. There is moderate peripheral oedema and moderate ascites with no signs of hepatomegaly.
Blood investigations were as follows:
Hb 102 g/l Platelets 250 * 109/l WBC 9.5 * 109/l Bilirubin 42 µmol/l ALP 135 u/l ALT 370 u/l γGT 70 u/l Albumin 32 g/l α-fetoprotein 15 kU/l
What is the most likely cause of this presentation?
Portal vein thrombosis Budd-Chiari syndrome > Hepatitis D infection Hepatocellular carcinoma Normal progression of the disease
This patient has developed acute liver decompensation. Hepatitis D infection is an uncommon but important cause of this presentation. It typically occurs in a patient with a history of stable chronic hepatitis B infection that suddenly acutely deteriorates.
Budd-Chiari syndrome (BCS) and portal vein thrombosis are not the correct options because it is unlikely to have any of them in the absence of hepatomegaly. In addition, the high level of the transaminase enzyme suggests viral infection rather than thrombus formation. Note that the transaminase enzyme should be only mildly elevated in BCS. Fever and nausea are also important symptoms that are usually present in BCS.
Hepatocellular carcinoma usually presents with very high levels of alpha-fetoprotein.
Hep C and Cryoglobulinaemia - Example Questions
A 48-year-old male with hepatitis C is admitted to the acute medical assessment unit having noticed a significant reduction in his urine output over the last few days. Urinalysis revealed haematoproteinuria, and his blood results are as follows:
Hb 9.8 g/dl
Platelets 75 * 109/l
WBC 12.1 * 109/l
Na+ 143 mmol/l
K+ 5.4 mmol/l
Urea 18.9 mmol/l
Creatinine 205 µmol/l
A renal biopsy was subsequently performed and microscopy of the sample showed generally enlarged and hypercellular glomeruli with an increase in mesangial cellularity and matrix. A histological diagnosis of membranoproliferative glomerulonephritis is made. What is the most likely underlying pathology for this finding?
> Cryoglobulinaemia Haemolytic uraemic syndrome Hepato-renal syndrome Systemic lupus erythematosus Thrombotic thrombocytopaenic purpura
This gentleman presents with acute kidney injury secondary to membranoproliferative glomerulonephritis. All of the listed options are recognised causes of membranoproliferative glomerulonephritis, but the key to this question is the patient’s history of hepatitis C which is known to be closely associated with cryoglobulinaemia.
Hep B and Risk of Cirrhosis - Example Question
A 42-year-old gentleman is reviewed in hepatitis clinic. He has recently been diagnosed with hepatitis B following sexual health screening. Currently, his liver function is normal and he has no other medical problems. He is concerned about developing cirrhosis of the liver. What marker is most useful in determining his risk for developing cirrhosis from hepatitis B?
Hepatitis B surface antibody Hepatitis B core antibody Hepatitis B core antigen > Hepatitis B DNA levels Hepatitis B e antibody
The correct answer is hepatitis B DNA levels. This will determine viral load and quantify the level of infection. The surface antibody is useful in determining immunity, the core antibody shows previous or current infection, whilst the e antibody is a marker of infectivity. All of the alternative choice aid with establishing if there is hepatitis B, if the patient has been vaccinated and if they are very infectious.
Hepatocellular Carcinoma - Most common causes?
In Europe = Hep C
Worldwide = Hep B
NB Hepatocellular Carcinoma usually has HIGH levels of alpha-fetoprotein on Ix
Hepatitis B - Fx, Cx, Mx
Hepatitis B is a double-stranded DNA hepadnavirus and is spread through exposure to infected blood or body fluids, including vertical transmission from mother to child. The incubation period is 6-20 weeks.
The features of hepatitis B include fever, jaundice and elevated liver transaminases.
Complications of hepatitis B infection chronic hepatitis (5-10%) fulminant liver failure (1%) hepatocellular carcinoma glomerulonephritis polyarteritis nodosa cryoglobulinaemia
Mx:
Management of hepatitis B
pegylated interferon-alpha used to be the only treatment available. It reduces viral replication in up to 30% of chronic carriers. A better response is predicted by being female, < 50 years old, low HBV DNA levels, non-Asian, HIV negative, high degree of inflammation on liver biopsy
whilst NICE still advocate the use of pegylated interferon firstl-line other antiviral medications are increasingly used with an aim to suppress viral replication (not in a dissimilar way to treating HIV patients)
examples include tenofovir and entecavir
Interpretation of Anti-HBs Levels post-immunisation
anti-HBs levels should be checked 1-4m after primary immunisation
Anti-HBs Level (mIU/mL)
> 100 - Indicates adequate response, no further testing required. Should receive booster at 5 yrs
10-100 - Suboptimal response, one additional vaccine dose should be given. If immunocompetent no further testing required
<10 - Non-responder. Test for current or past infection. Give further vaccine course (3 doses again) with testing following. If still fails to respond then HBIG required for protection if exposed
Unclear Hep B Test Results
HBsAg negative
Anti-HBc positive
Anti-HBs negative
4 possible interpretations
1) Resolved infection (most common reason)
2) False positive anti-HBc
3) Low level chronic infection
4) Resolving acute infection
Interpretation of Hep B Immunology
HBsAg = Hep B surface antigen
Anti-HBs = Hep B surface antibody
Anti-HBc = Total hepatitis B core antibody
IgM anti-HBc = IgM antibody to Hep B core antigen
IMMUNE DUE TO NATRUAL INFECTION:
HBsAg negative
Anti-HBc positive
Anti-HBs positive
IMMUNE DUE TO HEP B VACCINATION
HBsAg negative
anti-HBc negative
anti-HBs positive
ACUTE INFECTION
HBsAg positive
anti-HBc positive
anti-HBs negative
CHRONIC INFECTION HBsAg positive anti-HBc positive IgM anti-HBc negative anti-HBs negative
Hep B in Pregnancy
All pregnant women are offered Hep B screening
Babies born to mothers who are chronically infected with Hep B OR to mothers who have had acute Hep B during pregnancy should receive:
> a complete course of vaccination and Hep B immunoglobulin
If mother has:
HBsAg +ve, HBeAG +ve > Give newborn Hep B vaccine + Hep B immunoglobulin
If mother has HBsAG +ve, HBeAG +ve, anti-HBe > Give newborn Hep B vaccine
- Studies are currently evaluating role of antiretrovirals e.g. Lamivudine in latter part of pregnancy
- Little evidence to suggest C-sec decreases vertical transmission rates
NB Hep B cannot be transmitted via breast feeding (IN CONTRAST TO HIV)
Simeprevir and Hep C
Simeprevir is a NS3/4A hepatitis C virus (HCV) protease inhibitor, a cornerstone of modern management for hepatitis C. It is recommended by NICE for genotypes 1 and 4 in combination with interferon alpha and ribavirin.
