Hepatitis is the inflammation of the liver. It can occur due to innumerable causes such as alcoholic hepatitis, NAFLD, autoimmune hepatitis, drug induced hepatitis and of course viral hepatitis. This CCC will focus on viral hepatitis.
Furthermore there are numerous causes of viral hepatitis. Some of the causes are:
- Hepatitis A, B, C, D, E virus
- CMV
- EBV
- Adenovirus
We will primarily be looking at the hepatitis viruses (A-E) in this CCC…
😷 Presentation
Let’s discuss the general presentation of the hepatitis viruses as they are generally the same throughout.
Before we discuss the symptoms, we need to understand that there are 4 phases of the virus which produce different clinical features
Incubation phase
This phase is asymptomatic.
The timings of incubation differ for each virus (will be discussed below).
Prodromal phase
The prodromal phase is characterised by non-specific symptoms, such as:
- Flu-like symptoms
- Fever
- Fatigue
- Arthralgia
- Headache
- Pharyngitis
- GI symptoms
- Anorexia
- Nausea
- Vomiting
- RUQ discomfort
- Diarrhoea/constipation
- Skin symptoms
- Uriticaria
- Pruritus
Icteric phase
- Jaundice
- Pale stools and dark urine (due to cholestasis)
- Hepatosplenomegaly
- Lymphadenopathy
Convalescent phase
Symptoms start to improve and the individual may feel general malaise and hepatic tenderness.
A lot of these features may not be present in a large proportion of cases. We will discuss the specifics in the corresponding sections for the viruses, but generally the features are the same throughout.
HAV is a ssRNA hepatovirus (part of the picornoviridae) family. It is a more severe form in its presentation, but it carries a low risk compared to HBV and HCV as it does not lead to chronic infection.
Pathophysiology
- Transmission - It is transmitted by the faecal-oral route, usually through contamination of food or water. It is most prevalent in Subcontinental Asia and Africa due to poor sanitation. It may also be transmitted in men who have sex with men (MSM) and new infections occur when travelling to endemic regions.
It is transported across the intestinal epithelium and enters the liver via the mesenteric veins and portal system, through which it attaches to hepatocytes and enters the cells. It replicates within the cytoplasm before being released into bile and blood. They cause damage to the liver by inducing attacks from cytotoxic T cells or NK cells on infected hepatocytes.
⚠️ Risk factors
- Travellers to endemic areas
- MSM
- Occupational risk - lab workers, sewage workers, zoologists.
😷 Presentation
It’s incubation period ranges from 2-4 weeks.
The prodromal phase usually lasts 3-10 days.
The icteric phase lasts 1-3 weeks usually but can persist for more than 12 weeks in some. Only 8% of cases have cholestasis, however (with subsequent, jaundice, pruritus, pale stools, dark urine etc.).
The convalescent phase may take up to 6 months.
There is no risk of chronicity with HAV. It has a more acute course with more rapid onset, but subsequently resolves faster and does not persist.
🔍 Investigations
If HAV is suspected, we need to perform the following tests:
We look for 2 antibodies:
- HAV-IgM - detectable from 5 days after onset of symptom and peak during the icteric or early convalescent phase. They may remain positive for 45-60 days but sometimes up to 6 months.
- HAV-IgG - detectable 5-10 days after onset of symptoms but then remain persistent in the body even after complete resolution.
- Positive HAV-IgM and positive HAV-IgG is highly suggestive of acute hepatitis A.
- Negative HAV-IgM and positive HAV-IgG it is suggestive of previous infection or vaccination.
- Positive HAV-IgM and negative HAV-IgG is likely to be a false positive for HAV-IgM.
- Serum transaminases (ALT and AST) - significantly increased (>500units/L)
- Bilirubin - elevated
- ALP - elevate but not usually <2x of the upper limit.
- PT - it may be mildly prolonged.
🧰 Management
It is self-limiting and requires no treatment.
- Supportive treatment - analgesia and rest. Be careful of excessive paracetamol though.
An effective vaccine for HAV is available.
The HAV vaccine requires 2 doses. An initial dose and a subsequent dose after 6-12 months.
Who needs to be vaccinatied?
- People travelling to endemic areas >1 year old
- Chronic liver disease patients
- Haemophilia patients
- MSM patients
- IV drug users - there is risk of contamination with IV drugs.
- Occupational risk individuals - lab workers, sewage workers, individuals working with primates or staff at large residential institutions.
🚨 Complications
- Acute liver failure - very rare with about 0.4% of cases having ALF. It is characterised by severe vomiting worsening jaundice, encephalopathy, coagulopathy. These patients may be referred to liver transplantation centres as it may warrant transplantation.
HBV is a dsDNA virus a part of the hepadnaviridae family. It is the only dsDNA virus of the hepatitis viruses. It is the most prevalent globally but is concentrated in regions of sub-Saharan Africa, Asia and Pacific Islands.
The great concern with HBV is the risk of chronicity and progression.
Pathophysiology
- Transmission - It is transmitted parenterally (through blood, bodily fluids and vertical transmission). Groups at risk include IVDUs, MSM, sex workers, chronic liver disease and CKD, prison inmates and prison staff.
To fully understand the disease, let’s take a look at the structure and lifecycle for HBV:
HBV is covered in an outer lipid envelope, containing an icosahedral nucleocapsid inner core which is made up of proteins that enclose the HBV DNA as well as the enzyme DNA polymerase.
On these 2 layers we find 2 antigens:
- HBsAg (surface antigen) - consisting of small, medium and large proteins it is found on the lipid envelope.
- HBcAg (core antigen) - makes up the nucleocapsid.
The HBsAg binds to heparan sulfate proteoglycans (HSPGs) with low affinity and then binds to the sodium taurocholate co-transporting polypeptide (NTCP) with high affinity to then mediate endocytosis of HBV.
The virus then uncoats the nucleocapsid to release the HBV DNA which, at this stage, is relaxed circular DNA (rcDNA). This DNA is transported to the nucleus by microtubules and integrated into host DNA for transcription.
The rcDNA is then repaired and converted to covalently closed circular DNA (cccDNA). The cccDNA is used to transcribe the viral mRNAs, of which there are multiple:
- HBx - this produces the HBx protein which may be important for hepatocellular carcinoma carcinogenesis.
- PreS1 and preS2/S - these are used to recreate the HBsAg small, medium and large subunits.
- PgRNA - produces the viral DNA, DNA polymerase, as well as the HBcAg which all join together to recreate our nucleocapsid and its contents.
- Precore - produces the HBeAg which is an important marker used in serology as it is released into the blood.
As mentioned, the HBcAg will encapsidate the DNA and DNA polymerase to reform the nucleocapsid. The HBsAg will also reform and will then enclose the nucleocapsid to recreate the assembled virion which is known as the Dane particle.
The reason we have discussed the lifecycle is to give context for when we discuss the serological investigations for HBV.
😷 Presentation
Acute HBV infection
The incubation period is 6-20 weeks.
Around 70% of patients are asymptomatic. The symptoms of acute infection may last for 1-3 months. This includes jaundice, fever, malaise and cholestasis (dark urine, pale stools) or any of the other features previously mentioned.
Some complications of HBV infections include:
- Chronic HBV
- Acute liver failure (about 1%)
- Heptocellular carcinoma
- Glomerulonephritis
- Polyarteritis nodosa
- Cryoglobulinaemia
Chronic HBV infection
Chronic HBV infection risk is low (around 4% in healthy adults), but is higher in children as they cannot clear the infection. The viral DNA gets integrated into host DNA allowing it to replicate continuously.
Once again, it is mostly asymptomatic and the individuals are inactive carriers.
25% of individuals will have periodic reactivation.
15-20% will go on to develop cirrhosis. This poses as a major risk for the development of hepatocellular carcinoma (any deterioration in a patient with chronic hepatitis B should be suspicious for HCC).
There are often no physical signs either, however, after many years of infection there may be indicators of chronic liver disease such as:
- Spider naevi
- Clubbing
- Ascites
- Asterixis
🔍 Investigations
We should test for HBV when there are clinical features indicative of hepatitis B infection such as the acute symptoms or chronic patients who are showing signs of decompensation.
Abnormal LFTs may also be an indicator of liver injury that instigates further serological testing.
Acute hepatitis B
- Serum transaminases (ALT and AST) - significantly increased (>500units/L)
- Bilirubin - elevated
- ALP - elevated but usually <2x of the upper limit.
- PT - 5s or more is suggestive of severe hepatitis and 50s or more is indicative of acute liver failure.
Chronic hepatitis B
Often the only abnormality will be an elevated serum transaminases.
Before we start interpreting results, let’s look at the serological markers that are assessed and recap what they measure or indicate:
Surface antigen and antibody
- HBsAg - this is the surface antigen present on the outer surface. It is the first antigen that appears in the serum and lasts for up to 200 days (average of 75). If it is present, it always implies active infection. If it is present for more than 6 months it indicates chronic infection.
- Anti-HBs - HBsAg seroconversion refers to the development of anti-HBs antibodies which indicates clearance and resolution of the infection. It remains in the serum for life and indicates immunity. If anti-HBs is present without HBsAg then there could be 2 options:
- Cleared infection
- Vaccination against HBs
Core antigen and antibody
The HBcAg is not measured in serological testing, but the anti-HBc antibody is relevant clinically.
- Anti-HBc - depending on the type of antibody present we can elicit the time sine infection:
- Anti-HBc IgM - indicates recent infection (within 6 months) as IgM is the first antibody produced.
- Anti-HBc IgG - indicates resolved infection as well as those with chronic infection.
Envelope antigen and antibody
- HBeAg - as this is released into the serum during replication, it indicates active viral replication and risk of transmissibility. It is used to distinguish between active chronic infection and inactive chronic infection.
- Anti-HBe - the seroconversion of HBeAg indicates a transition from active → inactive disease (a carrier state). It remains in the serum for life and indicates acquired natural immunity.
There are patients who are HBeAg negative and anti-HBe positive with chronic infection that are seen to have a viral load (indicating active chronic infection that has mutated). This is known as immune escape and are the main pool for spread in the UK. This is why chronically infectious patients need to be screened annually to identify if this is occurring.
HBV-DNA
Quantification of HBV-DNA is performed in patients who have serological markers that indicate infection. It gives us an idea of the viral load that the patient is carrying.
A high viral load is associated with progression to cirrhosis and HCC and is expected in patients with active chronic infection.
In summary:
When screening, the initial testing should involve at least 2 markers:
- HBsAg
- Anti-HBc
If there is a positive HBsAg it indicates that there is an infection present. However, we need to take a look at anti-HBc to determine if it is acute or chronic.
- Positive anti-HBc IgM → acute infection.
- Negative anti-HBc IgM and positive anti-HBc (total/IgG) → chronic infection.
At-risk groups, patients receiving systemic chemotherapy and pregnant women should all be screened.
🧰 Management
The HepB vaccine is a part of the 6-in-1 vaccination routine. It is given to babies in 3 doses: 8 weeks, 12 weeks and 16 weeks. Infants have a 90% risk of contracting hepatitis B if the mother has an active infection, unless immunised at birth. However, in contrast to HIV, it cannot be transmitted by breastfeeding.
If an individual is requiring pre or post-exposure prophylaxis they should be given a rapid immunisation schedule which is done in 21 days.
At-risk groups should be vaccinated and those with occupational exposures should be assessed 1-4 months after the first vaccination to assess anti-HBs levels:
Anti-HBs levels | Response |
>100 | Adequate response. No further testing. Should receive booster in 5 years. |
10-100 | Suboptimal response. An additional vaccine should be given. |
<10 | Non-responder. Test for ongoing or past infection and repeat the vaccine course (3 doses). If it fails, we need to give hepatitis B immunoglobulin (HBIG) for protection. |
Anyone who is HBsAg positive should be referred to gastroenterology or infectious disease specialists with an interest in hepatology.
Pregnant women require assessment within 6 weeks.
It is also required to notify the health protection unit as it is a notifiable disease.
Acute hepatitis B management
Symptomatic management is advised while waiting for a referral.
- Analgesia - paraetamol, ibuprofen, or codeine (avoid in severe liver impairment).
- Anti-emetics - metoclopramide or cyclizine.
- Pruritus treatment - chlorphenamine as well as keeping cool and wearing loose clothing and avoiding hot baths/showers.
Chronic hepatitis B management
Before starting treatment, it is important to assess the individual’s risk of HIV exposure before starting treatment.
Anti-viral treatment is as follows:
- 🥇Peginterferon alfa-2a - is the recommended first-line option.
- Entecavir is an alternative
- Tenofovir disproxil/alafenamide are also alternatives.
Patients with decompensated cirrhosis should be considered for liver transplant.
HCV is an ssRNA virus part of the flavaviridae family. It is similar to HBV in many ways as it is transmitted parenterally. However, it has a much larger chance of chronicity which can also lead to HCC (leading cause of HCC in USA, Europe, Japan and South America).
Pathophysiology
With an acute infection, about 45% of patients will develop antibodies. However, the majority of patients are left with chronic HCV infection and progressive liver damage.
About 50% of hepatocytes get infected, however, with chronic infection the liver damage is not resulting from damage to cells directly, rather from local immune responses which cause fibrogenesis (through hepatic stellate cells) and subsequent cirrhosis → HCC. This progression is accelerated with chronic alcohol consumption and non-alcoholic steatohepatitis.
😷 Presentation
It has an incubation period of approximately 6-9 weeks.
Few patients actually develop features but it can result in features as with other hepatitis infections.
Patients with chronic infections have a 20-30% chance of developing cirrhosis and its subsequent features.
1-4% develop HCC.
🔍 Investigations
- 🥇 First-line/screening is done using HCV antibody immunoassay. About 90% are positive 3 months after infection, but it may take more months for others to become positive.
- 🏆HCV RNA - if anti-HCV testing is positive we can use RNA testing to confirm the diagnosis, calculate the viral load and assess the genotype of the virus.
- LFTs should also be used to assess severity of liver damage.
A FibroScan should be used to assess for cirrhosis while an ultrasound can be used to assess for HCC.
🧰 Management
Treatment involves referral to gastroenterology, hepatology or infectious disease for specialist management.
It is a notifiable disease, so we need to notify the health protection unit.
- Advise them on alcohol and smoking cessation - to reduce the risk of HCC and decompensated cirrhosis.
- Education on transmission and informing potential contacts.
Antiviral treatment involves using direct acting antivirals (DAAs). They are tailored to the specific viral genotype (there are 8 genotypes). DAAs are very successful with an 8-12 week regime. They are curative with about 95% clearance. It usually involves a treatment including protease inhibitors such as sofosbuvir.
We won’t discuss all the antivirals as this is quite specialist information.
Some complications of treatments include:
- Ribavirin - haemolytic anaemia, cough, teratogenic.
- Interferon alpha - flu-like symptoms, depression, fatigue, leukopenia, thrombocytopenia.
If the patient has end-stage liver failure → liver transplant.
HDV is a ssRNA virus transmitted parenterally that requires HBsAg to complete its replication and lifecycle. When occurring with a patient who is HBsAg positive → superinfection.
🚨 Superinfection is associated with a high risk of acute liver failure, chronic hepatitis and cirrhosis.
🔍 It is diagnosed through reverse polymerase chain reaction.
🧰 Intereferon is the current management option but there is not much evidence on it.
It is a notifiable disease.
HEV is an RNA hepevirus that is also transmitted through the faecal-oral route. It is rare in the UK and is not as severe as HAV (also transmitted through faecal oral route). No treatment is required and it self-resolves within a month. The only thing to be concerned about is that it causes significant mortality in pregnant women (about 20%).
It has an incubation period of 3-8 weeks.
It is also a notifiable disease.