Hepatitis E

Hepatitis E
Straight to the point of care
Last updated: Mar 13, 2024

Table of Contents
Overview 3
Summary 3
Definition 3
Theory 4
Epidemiology 4
Aetiology 5
Pathophysiology 5
Classification 5
Case history 6
Diagnosis 7
Approach 7
History and exam 13
Risk factors 14
Investigations 17
Differentials 20
Management 24
Approach 24
Treatment algorithm overview 27
Treatment algorithm 29
Primary prevention 36
Secondary prevention 36
Follow up 37
Monitoring 37
Complications 38
Prognosis 39
Guidelines 40
Diagnostic guidelines 40
Treatment guidelines 41
Online resources 42
References 43
Images 51
Disclaimer 52
Hepatitis E Overview
Summary
Hepatitis E virus (HEV) infection affects millions of people globally. It is most prevalent in Africa and Asia,
and is increasing in parts of Europe but declining in the US.
OVERVIEW
Transmission is through the faecal-oral route in the developing world and through locally acquired zoonotic
infection in the developed world.
Approximately 95% of patients with acute HEV infection have asymptomatic infection. If symptoms do occur,
they are non-specific and may include fatigue, anorexia, and nausea; if the patient develops jaundice, they
may also present with pruritus.
Diagnosis is made by detection of anti-HEV immunoglobulin M (anti-HEV IgM) and confirmed with HEV RNA
testing in serum or stool. Note that HEV RNA may be the only positive test in immunosuppressed patients.
Acute HEV infection is self-limiting in the vast majority of patients. Pregnant women and patients with
underlying chronic liver disease are at particular risk for acute liver failure. Immunosuppressed patients may
fail to clear the infection and are at risk for progressing to chronic hepatitis.
Treatment for acute HEV infection is supportive in the majority of cases. Severe infection may require
treatment with antiviral therapy to prevent progression to acute liver failure. Treatment options for chronic
HEV infection include reduction of immunosuppression if appropriate to do so, ribavirin, and peginterferon
alfa.
Definition
Hepatitis E is an infection of the liver caused by the hepatitis E virus (HEV).[1] HEV infection, although
the most common cause of acute viral hepatitis globally, results in asymptomatic infection in the majority
(possibly over 95%) of affected people.[2] [3] If symptomatic infection does occur, it usually causes an acute
self-limiting illness that is typically indistinguishable from other forms of acute viral hepatitis. However, rarely,
acute liver failure can occur (pregnant women are particularly at risk). Chronic HEV infection (which has
been defined as a persistence of HEV replication for 3 or more months) is almost exclusively limited to
immunosuppressed patients.[2] [4] [5]
HEV is an RNA virus that has historically been transmitted primarily via the faecal-oral route. The
improvement in living conditions in many parts of the world and migration patterns have changed the main
route of transmission from faecal-oral to zoonotic in these areas, leading to food-borne cases of infection.[1]
This topic covers HEV in adults.
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Mar 13, 2024.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
3
can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2024. All rights reserved.
Hepatitis E Theory
Epidemiology
The worldwide burden of HEV infection is likely to be underestimated due to several factors, including
limitations of data in studies due to poor sensitivity of older serological assays used to estimate
THEORY
seroprevalence.[14] These studies also focused on developing countries, where the faecal-oral route of
transmission predominates, and not on developed countries, where zoonotic infection is endemic.[2] The
improvement in living conditions in many parts of the world and migration patterns has changed the primary
route of transmission from faecal-oral to zoonotic.
HEV infection, although the most common cause of acute viral hepatitis globally, results in asymptomatic
infection in the majority (possibly over up to 95%) of affected people.[2] [3] Data from the World Health
Organization suggest that worldwide there are 20 million HEV infections annually, resulting in around 3.3
million symptomatic cases.[15] Symptomatic infection in adults in developing countries is most common in
those aged 44 years and younger; in these regions, infection is usually acquired via the faeco-oral route.[1] A
systematic review of data from 75 countries estimated that 12.4% of the global population (approximately 939
million individuals) has had past HEV infection, based on the presence of serum anti-HEV immunoglobulin G
(IgG) antibodies.[16]
In 2015 there were 44,000 deaths resulting from HEV infection.[15] The highest prevalence of HEV is in
Africa and Asia, particularly in developing countries with poor sanitation and inadequate water supply.[1]
HEV infection has a varying clinical and epidemiological profile depending on the location where infection
is acquired. Infection with HEV genotypes 1 and 2 is typically acquired by drinking faecally contaminated
water in endemic areas such as Africa and Asia (genotype 1), or Mexico and West Africa (genotype 2).
HEV infection acquired via the faeco-oral route is associated with high morbidity and mortality in pregnant
patients.[1] [2] [17] In developed countries, including the US and the UK, sporadic, non-travel-associated
cases of HEV infection are primarily caused by HEV genotype 3 and largely affect men >40 years of
age and immunocompromised people.[1] [18] Infection caused by genotype 4 is most commonly found
in China, Japan, and Taiwan.[1] Genotype 3 and genotype 4 infections are most commonly acquired by
ingestion of undercooked or uncooked meat (e.g., pork, wild boar, or deer) but can also be contracted via
close association with the animal reservoir, such as by farm workers or veterinarians.[1] [19] Infection with
genotypes 3 and 4 HEV is not associated with increased risk of severe illness or excess mortality in pregnant
patients.[2]
Hepatitis E is not common in the US, and most HEV infection is acquired through travel to an endemic
country.[1] In the US, the National Health and Nutrition Examination Survey (1988-1994) demonstrated a
seroprevalence of HEV antibody of 21%, but this had declined significantly by 2009-2010; reasons for the
decline are unclear.[20]
In parts of Europe, however, confirmed infection rates have increased, with cases of acute HEV infection
outnumbering cases of acute hepatitis A and hepatitis B virus infection, although this may be related to
testing strategies.[21] Based on seroprevalence and blood donor data, it is estimated that there are at least
2 million locally acquired HEV infections in Europe occurring annually.[21] [22] [23] Locally acquired HEV
is now the most common cause of acute viral hepatitis in many European countries.[2] Seroprevalence
rates in the general population of England are estimated to be around 13%, suggesting that 200,000 annual
infections occur per year, accounting for approximately 600-800 cases of hepatitis.[24] [25]
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Mar 13, 2024.
Hepatitis E Theory
Aetiology
An enterically transmitted viral infection similar to, but distinct from, hepatitis A virus (HAV) infection had
been suspected for many years before it was first identified in an HAV-immune individual in 1983 on electron
THEORY
microscopy of stool samples.[26] Subsequently, in 1990, a non-enveloped, single-stranded RNA virus 27-34
nanometres in diameter was isolated and cloned and named hepatitis E virus (HEV).[27]
Infection with HEV genotypes 1 and 2 is typically acquired by drinking faecally contaminated water in
endemic areas such as Africa and Asia, demonstrated by epidemic peaks during the rainy season.[1] [7]
HEV genotypes 3 and 4 are acquired by ingestion of contaminated and uncooked or undercooked meat
(e.g, pork, wild boar, or deer) or close association with the animal reservoir, such as by farm workers or
veterinarians.[1] [19] [28] [29] Genotype 7 (the most recently identified genotype) was detected in a liver-
transplant recipient who regularly consumed camel meat and milk.[8]
Although much less common, HEV infection can occur after transfusion of blood products and organ
transplantation.[22] [30] [31] [32][33] Note that these risks are not applicable universally: for example, in the
UK, blood donations are screened for HEV before transfusion. Vertical transmission is also a less common
mode of transmission.[34] People living in crowded camps or temporary housing, such as refugees or people
who are internally displaced, are also at greater risk of contracting HEV infection.[1]
Note that many people in the US and Europe will not have a readily identifiable risk factor for HEV infection;
any person presenting with an otherwise unexplained acute hepatitis could have HEV infection, as HEV
infection is endemic in most high-income countries.[2]
Pathophysiology
It remains unclear how HEV infection leads to hepatitis. Because HEV infection is often transmitted via
contaminated water or by ingestion of infected meat products by the faecal-oral route, intestinal replication of
the virus after ingestion has been postulated before travel in the portal circulation to the liver.[35] The virus is
not pathogenic, so the hepatitis is presumably a result of the immune response.[3] The incubation period for
HEV infection is around 15-60 days.[2]
HEV may affect other areas of the body, including neuronal, kidney, and placental tissue, which may help to
explain some of the extrahepatic manifestations of the condition.[9]
Classification
HEV genotype
Hepatitis E virus (HEV) is part of the Hepeviridae family, which consists of positive-stranded RNA viruses
that affect many species. The Orthohepevirus genus of this family includes all the mammalian and avian
HEV isolates and is divided into four subgroups, A-D.[6] Group A is further divided into eight genotypes, with
genotype 1 and 2 infecting humans and genotypes 3 and 4 infecting animals such as swine, deer, and non-
human primates that can transmit disease to humans through ingestion of meat, direct contact, and other
routes. Note that patients are not routinely screened for genotypes as a part of diagnosis.
• Genotype 1 is endemic in Africa and Asia. It is transmitted by the faecal-oral route through
contaminated water and by person-to-person contact.[1] [7]
5
Hepatitis E Theory
• Genotype 2 is endemic in Mexico and West Africa. It is transmitted by the faecal-oral route through
contaminated water.[1] [7]
• Genotype 3 is found as isolated cases in developed countries, such as the US, France, the
Netherlands, and the UK. It is primarily transmitted to humans through ingestion of uncooked or
THEORY
undercooked meat.[1] [2]

• Genotype 4 is found as sporadic cases in China, Taiwan, and Japan. It is primarily transmitted to
humans through ingestion of uncooked or undercooked meat.[1]
• Genotype 7 (the most recently identified genotype) was detected in a liver-transplant recipient who
regularly consumed camel meat and milk.[8]
Case history
Case history #1
A 49-year-old woman presents with several days of fatigue, loss of appetite, and abdominal pain. She
recently returned from a month-long culinary tour of Europe where she visited multiple wineries and farms
and tried various local dishes. Examination shows normal vital signs, scleral icterus, and a soft abdomen.
Laboratory studies show an alanine aminotransferase of 809 IU/L, a total bilirubin of 133.41 micromol/L
(7.8 mg/dL), and an international normalised ratio (INR) of 1.1. Serum IgM anti-hepatitis E antibodies are
positive.
Other presentations
Patients with HEV infection may present with an acute hepatitis that is usually self-limiting. Many
patients with acute infection can be asymptomatic, although acute liver failure can less commonly occur.
Extrahepatic manifestations are numerous but uncommon, and may include neurological conditions
(e.g., Guillain-Barré syndrome, neuralgic amyotrophy, meningitis), acute renal disease, haematological
dysfunction with haemolysis and thrombocytopenia, acute pancreatitis, thyroiditis, and myocarditis.[2] [9]
HEV infection in some groups is associated with significant mortality and morbidity. Acute HEV infection
in pregnancy in endemic areas can lead to acute liver failure in upwards of 20% of women.[10] The
mechanism behind this is unclear but may be exacerbated by malnutrition. Acute HEV infection in patients
with underlying liver disease or cirrhosis can also be particularly severe.[2] [11] A prolonged cholestatic
hepatitis where jaundice can last for more than 3 months has been noted in patients with acute HEV, but
complete recovery is the rule, usually within a few months and with clearance of HEV RNA.[12]
Chronic HEV infection is almost always seen in immunosuppressed patients, such as recipients of
solid organ transplants and those with HIV infection, and appears to be related to their impaired T-cell
response.[2] [13]
Hepatitis E Diagnosis
Approach
The majority of patients with acute HEV infection are asymptomatic. In patients who develop an acute
hepatitis (possibly less than 5% of all cases of HEV infection), the history should look for risk factors for
potential exposure to HEV - most commonly, living in or recent travel to endemic areas such as Africa or
Asia (transmission via the faecal-oral route due to genotype 1 or 2 infection), or via consumption of raw or
undercooked pork, wild boar, or deer (food-borne/zoonotic transmission due to genotype 3 or 4), particularly
in Europe.[1] [2] Many patients in developed countries will not have a readily identifiable risk factor so, in
these regions, any patient with an otherwise unexplained acute hepatitis could have HEV infection.[2]
If symptoms do occur with acute HEV infection, they are usually non-specific and may be indistinguishable
from other types of acute hepatitis.
• Symptomatic infection is most common in those aged 44 years and younger in developing countries,
where infection is usually acquired via the faeco-oral route.[1]
• In developed countries, symptomatic illness is most commonly seen in older men, which may indicate
the presence of underlying liver disease.[11]
• Progression to acute liver failure is rare, and is more of a concern in patients with existing chronic liver
disease or patients who are pregnant; it is therefore important to have a high index of suspicion for
HEV infection in pregnant patients who present with an acute hepatitis in endemic areas.[2]
• HEV infection acquired via the faeco-oral route is associated with high morbidity and mortality in
pregnant patients.[1] [2] [17]
Extrahepatic manifestations of HEV infection can occur after acute infection and with chronic disease. Most
significantly, there are a myriad of neurological syndromes associated with HEV; an acute hepatitis with
neurological symptoms should raise suspicion for HEV infection.
All patients who present with signs and symptoms of acute hepatitis or acute liver failure, immunosuppressed
patients, and patients with underlying liver disease with unexplained elevation of liver function tests should
be tested for HEV infection.[2] The incubation period after exposure for HEV is 2-8 weeks; HEV RNA can be
detected in stool about 3 weeks after infection and can last for approximately 6 weeks.[46] [47] Biochemical
DIAGNOSIS
and serological markers start to increase just prior to symptom onset.[2]
Progression to chronic liver disease is most commonly associated with patients who are immunosuppressed,
such as recipients of solid organ transplants, and has been defined as persistence of HEV replication for
3 or more months.[2] [4] [5] Chronic infection has only been associated with infection with HEV genotypes
3 and 4.[4] [48] Solid organ transplant recipients infected with HEV have a greater than 50% risk of
developing chronic HEV infection, which can progress to cirrhosis within several years.[38] [49] Chronic
infection has less commonly been associated with other immunosuppressed groups, such as people with
primary immunodeficiency, those with HIV who have low CD4 T lymphocyte counts, and those undergoing
chemotherapy (especially due to haematological malignancies).[2] [38]
Any cause of acute hepatocellular injury is a differential for acute or chronic HEV infection. For chronic HEV
infection, the differential diagnosis includes diseases seen in immunosuppressed patients, such as other viral
causes of hepatitis. Several severe diseases seen in pregnancy are also differentials of acute HEV infection
in pregnant individuals. See Differentials .
History
Acute HEV infection
7
If symptoms do occur with acute HEV infection they are usually non-specific, and may include:
• Malaise[2]
• Fatigue[2]
• Anorexia[2]
• Nausea[2]
• Vomiting[2]
• Abdominal pain[2]
• Pruritus[2]
• Arthralgia/arthritis[2]
• Diarrhoea.
Enquire about potential exposure to HEV in patients who present with acute hepatitis, such as travel to
or from endemic areas, or consumption of swine or deer, particularly in Europe.[1] Take a detailed history
regarding travel, sources of drinking water, consumption of uncooked or undercooked food, and recent
contact with any jaundiced people.[1]
• Infection with HEV genotypes 1 and 2 is typically acquired by drinking faecally contaminated water
in endemic areas, demonstrated by epidemic peaks during the rainy season.[1] [7]
• HEV genotypes 3 and 4 are acquired by ingestion of contaminated food or close association with
the animal reservoir, such as by farm workers or veterinarians.[19] [29]
• Although much less common, HEV infection can occur after transfusion of blood products or
following organ transplantation.[22] [30] [31] [32][33] These risks are not applicable universally: for
example, in the UK, blood donations are screened for HEV before transfusion.
• Vertical transmission can occur, but this is a less common mode of transmission.[34]
• People living in crowded camps or temporary housing, such as refugees or people who are
internally displaced, or those living in military camps, are at greater risk of contracting HEV
infection.[1] [40]
Ask about previous medical history as well as symptoms of extrahepatic manifestations of HEV, which
can occur after acute infection and with chronic disease. As there are myriad neurological syndromes
DIAGNOSIS
associated with HEV infection, an acute hepatitis with neurological symptoms should raise suspicion
for the condition. Conditions that have been observed in the context of hepatitis E are numerous, and
include:[2] [9]
• Neurological
• Guillain-Barré syndrome
• Neuralgic amyotrophy
• Meningitis
• Cranial nerve palsies
• Renal
• Glomerulonephritis
• Haematological
• Cryoglobulinaemia
• Thrombocytopenia
• Haemolysis
• Aplastic anaemia
• Other
• Acute pancreatitis
• Thyroiditis
• Myocarditis.
Acute liver failure/acute-on-chronic liver failure

Although the definition of acute liver failure varies globally, the most commonly used definition in the US
and Europe is: an illness duration of <26 weeks in a patient with no evidence of prior liver disease or
cirrhosis with any degree of mental status alteration (encephalopathy) and coagulopathy (international
normalised ratio [INR] ≥1.5).[50]
Acute liver failure is a rare sequela of acute HEV infection and is more of a concern in patients with
existing chronic liver disease (when symptoms occur in a patient with pre-existing liver disease, the term
'acute-on-chronic liver failure' is used).[2] [11] However, it is important to note that acute HEV infection in
pregnancy in endemic areas can lead to acute liver failure in upwards of 20% of women.[10]
Patients who progress to acute, or acute-on-chronic, liver failure may present with symptoms
including:[51] [52] [53]
• Abdominal pain
• Nausea
• Vomiting
• Malaise
• Confusion, changes in personality, or somnolence (due to hepatic encephalopathy).
See Acute liver failure .
DIAGNOSIS
Chronic HEV infection
Clinical presentation of chronic HEV infection has largely been found in patients with solid organ
transplantation, but has also been associated with other immunosuppressed groups, such as individuals
with HIV, patients with primary immunodeficiencies, and patients undergoing chemotherapy.[2] [13]
Chronic HEV infection is frequently asymptomatic in people who are immunosuppressed, and is typically
identified during investigation following abnormal biochemical liver function tests.
Solid organ transplant recipients infected with HEV have between a 50% and 70% risk of developing
chronic HEV infection, which can progress to cirrhosis within several years.[2] [38] [49] [54] Note that
in some countries, including the UK and Ireland, and some parts of Europe, blood samples from solid
organ donors are screened for HEV infection; this is performed post transplant to help inform clinical
management decisions in recipients. Chronic HEV infection that is untreated or fails treatment can cause
liver fibrosis and progress to cirrhosis. See Complications .
Physical examination
Acute HEV infection
9
In patients with acute HEV infection, examination may reveal jaundice, scleral icterus, and, in some
patients, right upper quadrant tenderness. Also be alert for signs of neurological syndromes associated
with acute HEV (see above).
Patient with jaundice

Garry Watson/Science Photo Library

DIAGNOSIS
The physical examination in most patients with chronic HEV will be normal. Note that patients with chronic
disease may progress to cirrhosis of the liver, and may develop stigmata of chronic liver disease. See
Complications .
Acute liver failure/acute-on-chronic liver failure

Patients who present with acute liver failure/acute-on-chronic liver failure may have similar signs to
those presenting with acute hepatitis infection; patients with acute liver failure may also have features of
hepatic encephalopathy evident on examination. Hepatic encephalopathy encompasses a spectrum of
neurological and psychiatric changes; initial signs and symptoms may be subtle.[55] Signs that may be
present on examination due to encephalopathy include:[55]
• Asterixis
• Hypertonia
• Hyperreflexia
• Clonus
• Rigidity.
Patients with acute hepatic failure may also have hepatomegaly, as well as right upper quadrant
tenderness. Less commonly patients may present with features of coagulopathy. See Acute liver failure .
Initial investigations
Test the patient for hepatitis E infection if they:[1] [2]
• Present with an acute hepatitis and have travelled from an area in which there is a hepatitis E
outbreak or where hepatitis E is endemic
• Have unexplained symptoms of liver injury, regardless of travel history, and test negative for
serological markers of hepatitis A, hepatitis B, hepatitis C, other hepatotropic viruses, and all other
causes of acute liver injury; see Hepatitis A , Hepatitis B , Hepatitis C
• Present with suspected drug-induced liver injury
• Are immunosuppressed and have unexplained abnormal liver function tests
• Have unexplained flares of chronic liver disease
• Present with neuralgic amyotrophy or Guillain-Barré syndrome
• Have abnormal liver function tests after receiving blood products (note this does not apply to those
who have received blood transfusions in countries where there is routine nucleic acid testing of
blood donations for HEV: for example, in the UK).
Also consider testing for HEV infection in patients with:[2]
• Encephalitis
• Myelitis.
Tests for HEV

Use a combination of nucleic acid amplification techniques (NAATs) and serological testing to confirm
HEV infection.[1] [2] [56]
HEV antibody (anti-HEV) and HEV RNA polymerase chain reaction (PCR) tests are the basic tests for
diagnosis of HEV infection and subsequent monitoring. However, availability of these tests may be limited
in some regions - follow your local protocol. In the US, for example, these tests can be ordered from the
DIAGNOSIS
Centers for Disease Control and Prevention. [CDC: hepatitis E information - laboratory testing requests]
(https://www.cdc.gov/hepatitis/hev/labtestingrequests.htm) Rapid tests for HEV infection detection are
also available.[15]
Always request anti-HEV immunoglobulin M (IgM) screening in immunocompetent patients with

suspected HEV.[2] [15] [56]
• Definitive diagnosis of HEV infection in endemic areas is usually based on serum anti-HEV IgM
antibody detection in immunocompetent patients.[15] [56] Anti-HEV IgM is usually detectable from
1 week to 2 months after exposure to the virus and typically persists for 3-4 months.[2] [56]
• Some organisations, such as the European Association for the Study of the Liver (EASL), also
recommend anti-HEV IgG screening alongside anti-HEV IgM.[2] Bear in mind, however, that anti-
HEV IgG positivity may reflect past infection. Anti-HEV IgG is detectable later in the clinical course
than anti-HEV IgM; the titre increases throughout the illness, and can persist for many years.[2]
If the patient is immunosuppressed, use other tests, such as reverse transcriptase polymerase chain
reaction (RT-PCR) for hepatitis E virus RNA detection in serum and stool (note these tests require
specialised testing facilities).[2] [15][25] [41] [56] Antibody detection is unreliable in transplant recipients
11
and other people who are immunosuppressed, due to delayed or impaired humoral response (which may
lead to false negative results).[2][25] [41] [56] [57] These approaches may also be helpful for diagnosis in
areas where HEV infection is less common, and to detect chronic HEV infection.[15]
• HEV RNA present in serum or stool indicates HEV infection and is often the only positive test in
immunosuppressed patients with chronic HEV infection.[56]
• HEV RNA is detectable around 3 weeks after onset of infection, and may persist for several weeks
after infection has cleared.[2] [17]
• Chronic HEV infection is defined by the persistence of HEV RNA for 3 or more months.[2] [4] [5]
• In practice, serum HEV RNA testing is often used in preference to stool analysis due to availability
and ease of testing; however, stool testing may be useful following treatment of chronic infection as
a negative stool HEV RNA is helpful to confirm treatment success.
Characterisation of liver status

Perform the following laboratory tests in all patients to characterise liver disease status:
• Full blood count

• Urea and electrolytes
• Coagulation profile
• Liver biochemistry, including:
• Aspartate aminotransferase (AST)

• Alanine aminotransferase (ALT)
• Alkaline phosphatase
• Total bilirubin (direct and indirect)
• Albumin.
Consider abdominal ultrasound as a first imaging test in patients who may have underlying liver disease,
are immunocompromised, or have chronic infection to evaluate the liver for the presence of fibrosis,
cirrhosis, and portal hypertension, and to exclude hepatocellular carcinoma.
DIAGNOSIS
Other investigations
Triphasic contrast computed tomography or contrast magnetic resonance imaging may be considered,
particularly in patients with advanced fibrosis or cirrhosis. Non-invasive methods of assessing liver fibrosis
(e.g., transient elastography using magnetic resonance or Fibroscan, fibrosis biomarkers) or liver biopsy
can be obtained in situations where there is a diagnostic dilemma, but should not be routinely required.
Consider specialist nephrology review for further renal investigation if the patient has recent deterioration
of renal function or significant proteinuria.[2] Renal manifestations of HEV infection include pre-renal
failure, glomerular disorders, and tubular and interstitial injury.[58]
Consider referral to a neurologist for further investigations if the patient presents with neurological
manifestations related to HEV infection.
History and exam

Key diagnostic factors
presence of risk factors (common)
• Key risk factors for acquiring HEV infection include living in or travelling to a geographical region
endemic for HEV infection; eating raw or undercooked pork, venison, or boar; and living in
overcrowded accommodation such as temporary housing or refugee camps.[1] [36] Hepatitis E may
also be acquired via vertical transmission.[39]
• Immunocompromised people are at increased risk of developing chronic HEV infection.
jaundice/scleral icterus (uncommon)

• May occur in some patients with acute HEV infection, following the initial incubation period of 2-8
weeks.[1]
• Jaundice may also be a feature of chronic HEV infection. Chronic HEV infection is most commonly
found in patients with solid organ transplantation, but has also been associated with other
immunosuppressed groups, such as individuals with HIV, those with primary immunodeficiencies, and
those receiving chemotherapy.[2]
• Jaundice with associated scleral icterus is also a feature of acute liver failure.
asterixis (uncommon)
• Asterixis may be seen in acute infection of patients who have no underlying antecedent chronic liver
disease. This sign is concerning as it may be an indicator of acute liver failure. Asterixis may also
present in patients with acute HEV infection who have underlying chronic liver disease, and can be
a sign of progression from compensated to decompensated cirrhosis. Asterixis describes negative
myoclonus (involuntary flapping hand movements) detected by extending the arms, dorsiflexing the
wrist, and spreading the fingers.
Other diagnostic factors
DIAGNOSIS
asymptomatic (common)
• The majority of patients with acute HEV infection are asymptomatic. It is likely that less than 5% of all
patients with acute infection present with an acute hepatitis.[2]
malaise (common)
• Acute HEV infection may present as a self-limiting flu-like illness. Malaise is a common symptom, as is
fatigue.[1] [15]
fatigue (common)
• Acute HEV infection may present as a self-limiting flu-like illness. Fatigue is a common symptom, as is
malaise.[1] [15]
right upper quadrant tenderness (uncommon)

• May occur in some patients with acute HEV infection, as well as in patients with acute liver failure.
13
fever (uncommon)
• Acute HEV infection may present as a self-limiting flu-like illness. Fever is an uncommon symptom, as
is anorexia, nausea/vomiting, and arthralgia/arthritis.[1] [15]
anorexia (uncommon)
• Acute HEV infection may present as a self-limiting flu-like illness. Anorexia is an uncommon symptom,
as is fever, nausea/vomiting, and arthralgia/arthritis.[1] [15]
nausea/vomiting (uncommon)
• Acute HEV infection may present as a self-limiting flu-like illness. Nausea/vomiting is an uncommon
symptom, as is fever, anorexia, and arthralgia/arthritis.[1] [15]
arthralgia/arthritis (uncommon)
• Acute HEV infection may present as a self-limiting flu-like illness. Arthralgia/arthritis is an uncommon
symptom, as is fever, anorexia, and nausea/vomiting.[1] [15]
abdominal pain (uncommon)

• May occur in some patients with acute HEV infection, as well as in patients with acute liver failure.
diarrhoea (uncommon)
• May occur in some patients with acute HEV infection.
neurological manifestations (uncommon)

• Extrahepatic manifestations of HEV infection can occur after acute infection and with chronic disease.
There are a myriad of neurological syndromes associated with HEV, including neuralgic amyotrophy,
Guillain-Barré syndrome, and meningoencephalitis; an acute hepatitis with neurological signs and
symptoms should raise suspicion for HEV infection.[2]
• Patients with acute liver failure may present with neurological symptoms and signs of encephalopathy,
which may include confusion, changes in personality, somnolence, and asterixis.[51] [52] [53]
DIAGNOSIS
signs of coagulopathy (uncommon)

• Patients with acute liver failure secondary to HEV infection may rarely present with signs of
coagulopathy such as bleeding.
Risk factors
Strong
born or living in or travel to geographic regions where HEV is endemic
• Living in or travelling to HEV-endemic areas, such as Mexico and countries in Africa and Asia,
increases the risk of acquiring the infection via faeco-oral transmission (mostly due to drinking
contaminated water), which usually occurs in developing countries, especially in regions where
sanitation is poor.[1] [36] In developed countries, such as in parts of France, the Netherlands, and the
UK, there is an increased risk of infection acquired by food-borne transmission, where sporadic cases
have occurred due to consumption of contaminated undercooked or raw pork, wild boar, or deer.[1]
• In regions where HEV infection is endemic, the case-to-infection ratio is estimated to be between 1:3
and 1:4.[37] Many cases in the US occur in people who have recently travelled to countries where the
infection is endemic.[1]
• In one study, 18 (38%) of 47 patients with acute hepatitis were positive for antibody to HEV (anti-HEV),
and 9 (50%) of these were positive for serum HEV RNA, with epidemiological and molecular analyses
strongly indicating that most cases of HEV infection originated from travel to HEV-endemic areas.[36]
immunosuppression
• Progression to chronic HEV infection is most commonly associated with patients who are
immunosuppressed, such as recipients of solid organ transplants.[15] Chronic HEV infection has only
been associated with genotypes 3 and 4 and is defined as persistence of HEV replication for 3 or more
months.[2][4] [5]
• Chronic infection has less commonly been associated with other immunosuppressed groups, such as
people with primary immunodeficiency, those with HIV who have low CD4 T lymphocyte counts, and
those undergoing chemotherapy (especially due to haematological malignancies).[2] [38]
infected mother (for fetus)

• Vertical transmission is associated with increased risk of HEV infection.[34]
• One study found that mother-to-child transmission was observed in 46.09% (59/128) of HEV IgM-
positive mothers.[39]
Weak
person-to-person transmission
• People living in crowded camps or temporary housing, such as refugees or people who are internally
displaced or those living in military camps, are at increased risk of contracting HEV infection.[1] [40]
occupational exposure
• HEV genotypes 3 and 4 can be acquired by close association with the animal reservoir, and therefore
occupations involving work with animals, such as farm workers and veterinarians, are at increased risk
DIAGNOSIS
of exposure to HEV.[19] [29]
• In one study of 859 healthy people, including pig farm workers, forestry workers, and individuals
without working contact with animals (control group), anti-HEV antibodies were detected in 26% of the
control population in comparison with 36% and 44% of forestry and pig farm workers, respectively.[29]
blood/blood products transfusion

• HEV infection after transfusion of blood products has been observed.[22] [30] [31] [32] Note that this
risk is not applicable universally; in some countries (e.g., the UK), blood donations are screened for
HEV before transfusion.
• In one study conducted in Brazil, 20.0% (n = 8/40) of multiply transfused thalassaemia patients were
found to be anti-HEV IgG positive compared with 11.0% (n = 10/91) of blood donors.[31]
organ transplantation (if organ donor is HEV-positive)

• HEV infection can occur in patients following solid organ transplantation.[33]
• Note that in some countries, including the UK and Ireland, and some parts of Europe, blood samples
from solid organ donors are screened for hepatitis E infection; this is performed post transplant to help
inform clinical management decisions in recipients.[25]
15
• In one study carried out in the UK that assessed the transmission of HEV infection in 9 organ
donors with detectable HEV plasma viral load who donated 14 kidneys and 6 livers to 20 recipients,
all liver recipients had demonstrable HEV RNA in plasma detected at various time points post
transplantation.[33]
DIAGNOSIS
Investigations
1st test to order
Test Result
serum antibody to HEV may be positive
• Request antibody to HEV (anti-HEV) IgM in all immunocompetent
patients as part of the initial evaluation.[2] [15] [56]
• • Definitive diagnosis of HEV infection in endemic areas is
usually based on serum anti-HEV IgM antibody detection in
immunocompetent patients.[15] [56] Anti-HEV IgM is usually
detectable from 1 week to 2 months after exposure to the virus
and typically persists for 3-4 months.[2] [56] Positive HEV IgM
suggests recent HEV infection. However, anti-HEV IgM tests
can also be negative in acute infection (i.e., in people who
are immunosuppressed due to delayed or impaired humoral
response).
• Some organisations, such as the European Association for
the Study of the Liver (EASL), also recommend anti-HEV IgG
screening alongside anti-HEV IgM.[2] Bear in mind, however,
that anti-HEV IgG positivity may reflect past infection. Anti-HEV
IgG is detectable later in the clinical course than anti-HEV IgM;
the titre increases throughout the illness, and can persist for
many years.[2]
HEV RNA nucleic acid amplification techniques (NAATs) positive for HEV
• If the patient is immunosuppressed, use NAATs such as reverse
transcriptase polymerase chain reaction (RT-PCR) for hepatitis E
virus RNA detection in serum and stool (note that these tests require
specialised testing facilities).[2] [15][25] [41] [56] Antibody detection
is unreliable in transplant recipients and other people who are
immunosuppressed, due to delayed or impaired humoral response
(which may lead to false negative results).[2][25] [41] [56] [57] HEV
DIAGNOSIS
RNA testing may also be helpful for diagnosis in areas where HEV
infection is less common, and to detect chronic HEV infection.[15]
• • HEV RNA present in serum or stool indicates HEV infection
and is often the only positive test in immunosuppressed
patients with chronic HEV infection.[56]
• HEV RNA is detectable around 3 weeks after onset of
infection and may persist for several weeks after infection has
cleared.[2] [17][47]
• Chronic HEV infection is defined by the persistence of HEV
RNA for 3 or more months.[2] [4][5]
• In practice, serum HEV RNA testing is often used in preference to
stool analysis due to availability and ease of testing; however, stool
testing may be useful following treatment of chronic infection as a
negative stool HEV RNA is helpful to confirm treatment success.
serological tests for other causes of viral hepatitis negative
• Request serological tests for hepatitis A infection, hepatitis B
infection, and hepatitis C infection in all patients as part of the initial
evaluation to exclude other viral causes of hepatitis. See Hepatitis A ,
Hepatitis B , Hepatitis C .
17
Test Result
liver biochemistries ALT, AST, alk phos,
bilirubin: may be elevated;
• Request in all patients as part of the initial evaluation:
albumin: may be low
• • Alanine aminotransferase (ALT)
• Aspartate aminotransferase (AST)
• Alkaline phosphatase (alk phos)
• Total bilirubin (direct and indirect)
• Albumin.
• In acute infection ALT and AST may be >1000 IU/mL. In chronic
infection ALT and AST may only be mildly elevated. Bilirubin
level may be elevated and albumin may be low in patients with
decompensated cirrhosis.
FBC may be low (particularly
platelet count) or normal
• • Haemoglobin/haematocrit
• White cell count and differential
• Platelet count.
• All parameters of the FBC may be decreased in patients with
cirrhosis and portal hypertension.
urea and electrolytes may be normal or
hyponatraemia and/or
high urea
• • Electrolytes
• Urea
• Creatinine.
• In patients with cirrhosis and ascites there may be electrolyte
disturbances including hyponatraemia. Metabolic parameters may be
deranged in severe acute infection, including infection in patients with
underlying cirrhosis.
DIAGNOSIS
coagulation profile may be normal or elevated

• • Prothrombin time (PT) and INR.
• In patients with acute liver failure or cirrhosis, levels may be elevated,
indicative of liver synthetic dysfunction.
Other tests to consider
Test Result
abdominal ultrasound may reveal coarsened
• Consider abdominal ultrasound as a first imaging test in patients who appearance of the
may have underlying liver disease, are immunocompromised, or have liver with irregular
contours and signs of
chronic infection, to evaluate the liver for the presence of fibrosis,
portal hypertension, or
cirrhosis, and portal hypertension, and to exclude hepatocellular
hepatocellular carcinoma
carcinoma.
• Ultrasound may be normal. In patients with cirrhosis, the liver may
look coarsened with irregular contours and there may be signs of
portal hypertension (which may include increased spleen longitudinal
diameter, oesophageal varices, or mild ascites).
CT/MRI may demonstrate cirrhotic
liver morphology and
• Consider triphasic contrast CT scan or contrast MRI of the abdomen
evidence of portal
in patients with advanced fibrosis or cirrhosis.
hypertension
liver biopsy may demonstrate

inflammation or fibrosis
• Histological examination following biopsy is not routinely obtained
in cases of hepatitis E infection but may be required if there is a
diagnostic dilemma.
DIAGNOSIS
19
Differentials
Condition Differentiating signs / Differentiating tests

symptoms
Acute viral hepatitis A • There may be no differences • Serum hepatitis A virus IgM
in signs and symptoms. antibody will be positive.
Acute viral hepatitis B • There may be no differences • Serum hepatitis B surface

in signs and symptoms. antigen and serum antibody
to hepatitis B surface antigen
and/or hepatitis B core IgM
will be positive.
• Serum hepatitis B virus DNA
may be positive.
Acute viral hepatitis C • There may be no differences • Serum hepatitis C virus

in signs and symptoms. (HCV) antibody and HCV
RNA may be positive.
Acute viral hepatitis D • Symptoms and signs can • Serum hepatitis D virus
be identical to those of other (HDV) RNA and antibodies
acute viral hepatitis. Note to hepatitis D (anti-HDV) IgM
that Hepatitis D infection can and IgG may be positive.
only occur in the presence of
hepatitis B infection.
Drug- or toxin- induced • May have a history of • Liver biopsy may show the
hepatitis/drug-induced exposure to drugs or toxins. features of hepatocellular,
liver injury (DILI) • Should be considered as cholestatic, or mixed
a differential, especially in pattern of injury, including
older patients who may be cholestasis.
on multiple drug treatments.
In a cohort study of UK
patients with 'criterion-
DIAGNOSIS
referenced' DILI, it was found

that in 13% the diagnosis of
DILI was erroneous, as the
patients had acute hepatitis
E.[59]
Acute alcoholic hepatitis • History of moderate/heavy • Aspartate aminotransferase

alcohol consumption. to alanine aminotransferase
• Hepatomegaly and jaundice (AST:ALT) ratio >2:1 in up to
are found in around 95% and 70% of cases.
55% of people presenting • Elevated gamma-glutamyl
with alcoholic hepatitis, transferase (GGT).
respectively. • Positive ethyl glucuronide
(ETG).
• Positive phosphatidylethanol
(PETH).
• FBC may show anaemia,
leukocytosis, and/or
thrombocytopenia.
• Negative viral hepatitis
serology.

symptoms
• Liver biopsy may show
steatosis, ballooning
hepatocytes, Mallory
hyaline, lobular neutrophilic
infiltration, with or without
pericellular fibrosis.
Autoimmune hepatitis • May have an associated • There may be increased

lymphadenopathy. There levels of serum globulin,
may be a history of other anti-nuclear antibody, anti-
autoimmune diseases, smooth muscle antibody,
such as thyroiditis, type 1 liver/kidney microsomal
diabetes, coeliac disease, antibodies, and/or antibodies
and ulcerative colitis.[60] [61] against soluble liver antigen/
liver pancreas antigen. Liver
histology may show interface
hepatitis with plasma cell
infiltrates.
• Negative viral hepatitis
serology.
Cytomegalovirus (CMV) • Clinical features of viral • Negative serology results

infection hepatitis with no history of for all types of viral hepatitis.
exposure to other organisms Atypical lymphocytes tend
that can cause hepatitis. to be present. CMV IgM
and IgG positive. CMV
polymerase chain reaction in
blood positive.
Epstein-Barr virus (EBV) • Clinical features of viral • Negative serology results

infection hepatitis with no history for all types of viral hepatitis.
of exposure to other Atypical lymphocytes tend to
organisms that can cause be present.
hepatitis; classically display • EBV IgM and IgG positive.
DIAGNOSIS
lymphadenopathy and
splenomegaly in EBV
infection.
Herpes simplex virus • Clinical features of viral • Negative serology results

infection hepatitis with no history of for all types of viral hepatitis.
exposure to other organisms Mainly a clinical diagnosis
that can cause hepatitis; (aided by presence of typical
may display characteristic muco-cutaneous lesions).
cutaneous ulceration. A liver biopsy confirms
diagnosis.
Wilson's disease • There may be associated • Increased 24-hour urinary

behavioural abnormalities copper, decreased serum
(such as loss of memory, ceruloplasmin, and Kayser-
anxiety, disinhibition), Fleischer rings on slit lamp
dysarthria, and presence eye examination.
of Kayser-Fleischer rings
(gold-brown corneal
pigments representing
21

symptoms
copper deposition) on eye
examination.
Metabolic dysfunction- • Often associated • Abdominal ultrasound may

associated steatotic liver with features of the show an echogenic liver.
disease (MASLD) metabolic syndrome • Ferritin may be elevated
(obesity, hypertension, with a normal transferrin
hyperlipidaemia, type 2 saturation.
diabetes mellitus). • Liver biopsy demonstrates
features of non-alcoholic
fatty liver disease with or
without excess iron.
Acute ischaemic hepatitis • Typically occurs in patients • ECG may show features
at risk for hypotension or of myocardial ischaemia or
ischaemia, including shock, infarction.
heart failure, or vascular • Chest x-ray and
insufficiency. Patients may echocardiogram may show
have symptoms of ischaemia features of congestive heart
such as acute heart failure, failure.
shock, or sepsis. • Doppler ultrasound of
liver may show portal
vein thrombosis or acute
occlusion of hepatic artery.
Biliary disease • May have fever, right upper • Elevated alkaline

quadrant pain, pruritus, dark phosphatase and bilirubin
urine, pale stool, weight loss. levels.
• Abdominal imaging may
show biliary dilation,
stricture, or obstruction.
• Anti-mitochondrial antibody
will be positive in primary
biliary cholangitis.
DIAGNOSIS
• Liver biopsy may show

biliary or cholestatic disease.
Acute fat ty liver of • Pregnant patient may • Diagnosis of exclusion

pregnancy (AFLP) present with jaundice. of other diseases with
characteristic symptoms and
signs in pregnant patients.
Haemolysis, elevated liver • Severe form of pre- • Reduced haemoglobin,

enzymes, low platelets eclampsia characterised by low or normal haematocrit,
(HELLP) syndrome haemolysis, also expressed thrombocytopenia.
as microangiopathic • Peripheral blood smear may
haemolytic anaemia, show schistocytes, burr cells;
elevated liver enzymes, and polychromasia may be seen
low platelets. secondary to haemolysis
and are diagnostic.
• Coagulopathy
(hypofibrinogenaemia,
prolonged prothrombin time,
low antithrombin) is usually
present in later stages of
disease.

symptoms
• Hypoglycaemia,
leukocytosis, and elevated
LDH levels may be
present. There may also
be haemoconcentration,
metabolic acidosis,
increased ammonia, and
elevated serum creatinine.
DIAGNOSIS
23
Hepatitis E Management
Approach
Treatment of HEV infection will depend on the clinical situation, particularly if the patient is
immunosuppressed. Acute HEV infection typically does not require treatment other than supportive care
as it resolves spontaneously in almost all patients.[1] [2] However, it is important to note that acute HEV
infection in pregnancy in endemic areas can lead to acute liver failure in upwards of 20% of women.[10]
Acute HEV infection in solid organ transplant recipients has been shown to resolve spontaneously in over
30% of cases; a reduction of immunosuppression in these patients should be considered wherever possible
to assist with viral clearance.[25] [54] There is no specific treatment for acute hepatitis E, but antiviral therapy
with ribavirin may be considered in patients with severe acute HEV infection to prevent progression to hepatic
decompensation, and in patients with acute-on-chronic liver failure.[2]
In people with chronic HEV infection, such as recipients of solid organ transplants, treatment may involve
adjustment/reduction of immunosuppression in the first instance, with the addition of ribavirin if HEV infection
persists.[2] [25]
If indicated, ribavirin is given for 3 months, but can be extended to 6 months if HEV remains detectable in
serum or stool following 3 months of treatment.
Treatment with peginterferon alfa may be considered in liver transplant recipients on a case-by-case basis if
HEV RNA is still positive after 6 months of ribavirin.[2] [25]
Consider specialist nephrology review for renal investigation if the patient has recent deterioration of renal
function or significant proteinuria.[2]
Consider referral to a neurologist if the patient has neurological manifestations related to HEV infection.
Acute HEV infection

For acute HEV infection, give supportive care, alongside monitoring of liver enzymes and liver function.
This is typically all that is required if the patient is immunocompetent.[2]
• Advise the patient to rest, consume adequate nutrition and fluids, avoid drinking alcohol, and
check with their physician before taking drugs that may potentially cause hepatic damage (e.g.,
paracetamol).[1]
• Counsel the patient on hand hygiene to prevent transmission of HEV, particularly with respect to
food handling practices.
Some patients, such as those with chronic liver disease, people with weakened immune systems, and
older people, can experience more severe infection. These patients may require closer observation to
monitor for deterioration in liver function.[32]
Consider reduction of immunosuppression therapy (wherever possible) in patients with solid organ
transplant who have acute HEV infection, to assist with viral clearance.[25] [54] Acute HEV infection in
solid organ transplant recipients has been shown to resolve spontaneously in over 30% of cases.[25] [54]
MANAGEMENT
Consider treatment with ribavirin for patients with severe acute HEV infection, patients who are at
increased risk of progression to hepatic decompensation, and those with acute-on-chronic liver failure.[2]
• Case reports of ribavirin in acute HEV infection (or acute HEV infection occurring in underlying
liver disease) suggest that liver enzymes may rapidly normalise, with HEV RNA levels becoming
undetectable within days of initiation of treatment.[62]
• Women of childbearing age, and men who may have sex with women of childbearing age, should
be counselled regarding the use of contraception during treatment with ribavirin and after treatment
has stopped.
Refer patients who develop signs that may be suggestive of acute liver failure to a transplant centre for
monitoring and consideration of a liver transplant.[63] See Acute liver failure .
Pregnant women
Acute HEV infection in pregnancy in endemic areas can lead to acute liver failure in upwards of 20% of
women.[10]
Perform frequent monitoring of signs and symptoms as well as biochemical parameters in all pregnant
women with acute HEV infection, under the combined management of the obstetric and specialist
hepatology teams. Consider hospital admission for pregnant women with symptomatic acute HEV
infection on a case-by-case basis.[1] [15] Based on clinical experience in practice, indications for
admission include evidence of deteriorating liver function and concern for fetal viability. Also consider
hospital admission for pregnant women with solid organ transplant who have acute HEV infection (seek
expert advice).
Treatment in a high-dependency treatment setting may be required for symptomatic pregnant patients,
and transfer to a transplant centre will be required if signs of liver failure are present.[2]
If hospital admission is not indicated:
• Advise the patient to rest, avoid drinking alcohol, consume adequate nutrition and fluids, and
check with their physician before taking drugs that may potentially cause hepatic damage (e.g.,
paracetamol)[1]
• Counsel the patient on hand hygiene to prevent transmission of HEV, particularly with respect to
food handling practices.
Note that ribavirin is contraindicated in pregnancy.

The vast majority of patients with chronic HEV infection are immunosuppressed, with the condition most
commonly being found in recipients of solid organ transplants. The goal of treatment in patients with
chronic HEV infection is sustained viral eradication.
Where possible, decrease immunosuppression therapy at diagnosis of chronic HEV infection in recipients
of solid organ transplants.[2] [25] [41]
• A systematic review of data from 21 studies of immunocompromised patients with HEV infection
showed that reduction of immunosuppressive drugs induced clearance of HEV in 32% of
MANAGEMENT
patients.[64]
• A retrospective analysis of data from 17 centres from the US and Europe, including 85 recipients
of solid organ transplants who were chronically infected with HEV, noted that 32.1% achieved viral
clearance when the dose of immunosuppressive drugs was reduced.[54]
25
Give ribavirin for 3 months to patients in whom HEV replication persists 3 months after detection of HEV
RNA, and to transplant recipients with chronic HEV infection in whom reduction of immunosuppression
is not possible or is unsuccessful.[2] [41] There have been no placebo-based trials for the use of ribavirin
in chronic HEV infection; treatment recommendations are based on the results of case reports and case
series.[57] [65] [66][67]
• One meta-analysis of the effect of ribavirin in 395 immunosuppressed patients with chronic HEV
infection found that 301 patients (76%) achieved a sustained viral response following 3 months of
therapy.[64]
• A retrospective, multi-centre case series assessing the effects of ribavirin in 59 solid organ
transplant recipients treated for a median of 3 months demonstrated a 78% sustained viral
response rate in these patients.[67] Another study of 6 recipients of kidney transplants with chronic
HEV infection found that HEV RNA was undetectable in the serum of all patients after 3 months of
ribavirin.[57]
• Ribavirin is associated with adverse effects, particularly dose-dependent anaemia. Regular
monitoring of FBCs is required in all patients, and a dose reduction, with or without transfusion,
may be required in patients who develop anaemia.[2] [25]
Regularly assess response to ribavirin with serum alanine aminotransferase (ALT) and HEV RNA in stool
and serum.
• Stop ribavirin if HEV RNA in both stool and serum are negative as this indicates a sustained viral
response; note that stool HEV RNA may remain positive long after serum HEV RNA is negative,
hence the requirement for stool HEV testing to avoid relapse.
• Continue ribavirin for a further 3-6 months if there is persistence of HEV RNA in either stool or
serum following the initial 3 months of treatment.[2] [41]
Consider switching to peginterferon alfa 2a in liver transplant recipients, on a case-by-case basis, if HEV
RNA is still positive after 6 months of ribavirin.[2][25] [41] Peginterferon alfa 2a may also be considered as
an alternative to ribavirin in these patients, on a case-by-case basis, if ribavirin is not tolerated.[41]
• Peginterferon alfa may be considered based on efficacy in small case series, but is associated with
the risk of rejection in solid organ transplant recipients except liver transplant.[2]
• Treatment of these patients with peginterferon alfa should only be performed at, or in consultation
with, a transplant centre.
In immunosuppressed patients who have not had a solid organ transplant, such as those with HIV or
haematological disorders, a handful of case reports/small series have shown some efficacy with treatment
with peginterferon alfa, ribavirin, or a combination of the two drugs.[68] [69] [70]
• One systematic review of studies that identified 13 immunosuppressed patients with chronic HEV
infection who were treated with peginterferon alfa noted a rapid virological response in four patients
(31%); 11 patients (84%) achieved sustained viral response.[64] However, acute transplantation
rejection occurred in two patients during treatment.[64]
Peginterferon alfa may cause or aggravate fatal or life-threatening infectious, neuropsychiatric,
MANAGEMENT
autoimmune, and ischaemic disorders. Monitor patients closely.
Advise all patients with chronic HEV to avoid drinking alcohol, and check with their physician before taking
drugs that may potentially cause hepatic damage (e.g., paracetamol).[1]
Counsel the patient on hand hygiene to prevent transmission of HEV, particularly with respect to food
handling practices.
Pregnant women
Monitor pregnant women with chronic HEV infection, under the combined management of the obstetric
and specialist hepatology teams. Consider hospital admission on a case-by-case basis. Based on clinical
experience in practice, indications for admission include evidence of deteriorating liver function and
concern for fetal viability.
Provide pregnant women with supportive care, if needed. Advise the patient to avoid drinking alcohol,
consume adequate nutrition and fluids, and check with their physician before taking drugs that may
potentially cause hepatic damage (e.g., paracetamol).[1]
Counsel the patient on hand hygiene to prevent transmission of HEV, particularly with respect to food
handling practices. Note that ribavirin and peginterferon alfa are contraindicated in pregnancy due to their
potential teratogenic effects.
Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute ( summary )
acute HEV infection
non-pregnant 1st supportive care
adjunct immunosuppression therapy taper
adjunct ribavirin
adjunct liver transplantation
pregnant 1st supportive care

MANAGEMENT
27
Ongoing ( summary )
chronic HEV infection: non-pregnant
with solid organ 1st immunosuppression therapy taper

transplant
plus supportive care
2nd ribavirin
3rd peginterferon alfa
without solid organ 1st ribavirin and/or peginterferon alfa

transplant
chronic HEV infection: pregnant
1st supportive care

MANAGEMENT
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute
acute HEV infection
non-pregnant 1st supportive care
» Acute HEV infection typically does not require

treatment other than supportive care as it
resolves spontaneously in almost all patients.[1]
[2]
» Advise the patient to rest, consume adequate

nutrition and fluids, avoid drinking alcohol, and
check with their physician before taking drugs
that may potentially cause hepatic damage (e.g.,
paracetamol).[1]
» Counsel the patient on hand hygiene to

prevent transmission of HEV, particularly with
respect to food handling practices.
» Some patients, such as those with chronic

liver disease, people with weakened immune
systems, and older people, can experience more
severe infection. These patients may require
closer observation to monitor for deterioration in
liver function.[32]
adjunct immunosuppression therapy taper
Treatment recommended for SOME patients in
selected patient group
» Consider reduction of immunosuppression
therapy (wherever possible) in patients with solid
organ transplant who have acute HEV infection,
to assist with viral clearance.[25] [54] Acute HEV
infection in solid organ transplant recipients has
been shown to resolve spontaneously in over
30% of cases.[25] [54]
adjunct ribavirin
Primary options
» ribavirin: 600-800 mg/day orally given in 1-2

divided doses
MANAGEMENT
The optimal dosing regimen has not been

established. A dose range of 400 mg/day to
1000 mg/day has been reported in studies.
29
Acute
» Consider treatment with ribavirin for patients
with severe acute HEV infection, patients who
are at increased risk of progression to hepatic
decompensation, and those with acute-on-
chronic liver failure.[2]
» Case reports of ribavirin in acute HEV infection

(or acute HEV infection occurring in underlying
liver disease) have suggested that liver enzymes
may rapidly normalise, with HEV RNA levels
becoming undetectable within days of initiation of
treatment.[62]
» Ribavirin is associated with adverse effects,

particularly dose-dependent anaemia. Regular
monitoring of FBCs is required in all patients,
and dose reduction, with or without transfusion,
may be required in patients who develop
anaemia.[2] [25]
» Women of childbearing age, and men who

may have sex with women of childbearing age,
should be counselled regarding the use of
contraception during treatment with ribavirin and
after treatment has stopped.
» Assess response to ribavirin with serum

alanine aminotransferase (ALT) and HEV RNA
in stool and serum. Stop ribavirin if HEV RNA
in both stool and serum are negative as this
indicates a sustained viral response. Continue
ribavirin for a further 3-6 months if there is
persistence of HEV RNA in either stool or serum
following the initial 3 months of treatment.[2] [41]
» Refer patients who develop signs that may be
suggestive of acute liver failure to a transplant
centre for monitoring and consideration of a liver
transplant.[63] See Acute liver failure .
pregnant 1st supportive care
» Acute HEV infection typically does not require

treatment other than supportive care as it
resolves spontaneously in almost all patients.[1]
[2] However, it is important to note that acute
HEV infection in pregnancy in endemic areas
can lead to acute liver failure in upwards of 20%
of women.[10]
MANAGEMENT
» Perform frequent monitoring of signs and

symptoms as well as biochemical parameters
in all pregnant women with acute HEV infection,
under the combined management of the
obstetric and specialist hepatology teams.
Acute
» Consider hospital admission for pregnant
women with symptomatic acute HEV infection on
a case-by-case basis.[1] [15] Based on clinical
experience in practice, indications for admission
include evidence of deteriorating liver function
and concern for fetal viability. Also consider
hospital admission for pregnant women with
solid organ transplant who have acute HEV
infection (seek expert advice).
» If hospital admission is not indicated, advise

the patient to rest, consume adequate nutrition
and fluids, avoid drinking alcohol, and check
with their physician before taking drugs that
may potentially cause hepatic damage (e.g.,
paracetamol).[1] Counsel the patient on hand
hygiene to prevent transmission of HEV,
particularly with respect to food handling
practices.
» Acute HEV infection in pregnancy in endemic
areas can lead to acute liver failure in upwards of
20% of women.[10]
» Treatment in a high-dependency treatment

setting may be required for symptomatic
pregnant patients, and transfer to a transplant
centre will be required if signs of liver failure are
present.[2]
MANAGEMENT
31
Ongoing
chronic HEV infection: non-pregnant
with solid organ 1st immunosuppression therapy taper

transplant
» Where possible, decrease immunosuppression
therapy at diagnosis of chronic HEV infection in
recipients of solid organ transplants.[2] [25] [41]
» A systematic review of data from 21

studies of immunocompromised patients
with HEV infection showed that reduction of
immunosuppressive drugs induced clearance of
HEV in 32% of patients.[64]
» A retrospective analysis of data from 17

centres from the US and Europe, including
85 recipients of solid organ transplants who
were chronically infected with HEV, noted that
32.1% achieved viral clearance when the dose of
immunosuppressive drugs was reduced.[54]
Treatment recommended for ALL patients in
» Advise all patients with chronic HEV to avoid
drinking alcohol and check with their physician
before taking drugs that may potentially cause
hepatic damage (e.g., paracetamol).[1]

2nd ribavirin
Primary options

divided doses
» Give ribavirin for 3 months to transplant

recipients with chronic HEV infection in whom
reduction of immunosuppression is not possible
or is unsuccessful.[2] [41]
» There have been no placebo-based trials for

the use of ribavirin in chronic HEV infection;
MANAGEMENT
treatment recommendations are based on the

results of case reports and case series.[57] [65]
[66][67]
» One meta-analysis of the effect of ribavirin in

395 immunosuppressed patients with chronic
Ongoing
HEV infection found that 301 patients (76%)
achieved a sustained viral response following 3
months of therapy.[64]
» A retrospective, multi-centre case series

assessing the effects of ribavirin in 59 solid
organ transplant recipients treated for a median
of 3 months demonstrated a 78% sustained viral
response rate in these patients.[67] Another
study of 6 recipients of kidney transplants with
chronic HEV infection found that HEV RNA was
undetectable in the serum of all patients after 3
months of ribavirin.[57]

anaemia.[2] [25]
» Women of childbearing age, and men who

may have sex with women of childbearing age,
should be counselled regarding the use of
contraception during treatment with ribavirin and
after treatment has stopped.


3rd peginterferon alfa
Primary options
MANAGEMENT
» peginterferon alfa 2a: 180 micrograms

subcutaneously once weekly
» Consider switching to peginterferon alfa 2a

in liver transplant recipients, on a case-by-case
basis, if HEV RNA is still positive after 6 months
33
Ongoing
of ribavirin.[2][25] [41] Peginterferon alfa 2a may
also be considered as an alternative treatment
option to ribavirin in these patients, on a case-
by-case basis, if ribavirin is not tolerated.[41]
» Peginterferon alfa may be considered

based on efficacy in small case series, but
is associated with the risk of rejection in
solid organ transplant recipients except liver
transplant.[2] Treatment of these patients with
peginterferon alfa should only be performed at,
or in consultation with, a transplant centre.
» A systematic review of studies that

identified 13 immunosuppressed patients with
chronic HEV infection who were treated with
peginterferon alfa showed that a rapid virological
response was noted in four patients (31%),
and 11 patients (84%) achieved sustained viral
response.[64] However, acute transplantation
rejection occurred in two patients during
treatment.[64]
» Peginterferon alfa may cause or

aggravate fatal or life-threatening infectious,
neuropsychiatric, autoimmune, and ischaemic
disorders. Monitor patients closely.

without solid organ 1st ribavirin and/or peginterferon alfa
transplant
Primary options

divided doses
-and/or-
» peginterferon alfa 2a: 180 micrograms
MANAGEMENT
subcutaneously once weekly
» In immunosuppressed patients who have

not had a solid organ transplant, such as
those with HIV or haematological disorders, a
handful of case reports/small series have shown
Ongoing
some efficacy with treatment with ribavirin,
peginterferon alfa, or a combination of the two
drugs.[68] [69] [70]

anaemia.[2] [25] Women of childbearing age,
and men who may have sex with women
of childbearing age, should be counselled
regarding the use of contraception during
treatment with ribavirin and after treatment has
stopped.

» Peginterferon alfa may cause or

aggravate fatal or life-threatening infectious,
neuropsychiatric, autoimmune, and ischaemic
disorders. Monitor patients closely.

chronic HEV infection: pregnant
1st supportive care
» Monitor pregnant women with chronic HEV

infection, under the combined management of
the obstetric and specialist hepatology teams.
Consider hospital admission on a case-by-case
basis. Based on clinical experience in practice,
indications for admission include evidence of
MANAGEMENT
deteriorating liver function and concern for fetal

viability.
» Provide pregnant women with supportive care,

if needed. Advise the patient to avoid drinking
alcohol, consume adequate nutrition and fluids,
35
Ongoing
and check with their physician before taking
drugs that may potentially cause hepatic damage
(e.g., paracetamol).[1]

prevent transmission of HEV, particularly
with respect to food handling practices.
Note that ribavirin and peginterferon alfa are
contraindicated in pregnancy due to their
potential teratogenic effects.
Primary prevention
Because HEV infection is typically acquired by the faecal-oral route in the developing world, travellers to
endemic regions should take precautions to avoid exposure to potentially contaminated water, and avoid
eating raw vegetables, fruit, or undercooked meat; note that boiling and chlorination of water will inactivate
HEV.[1] Similarly, due to zoonotic transmission, particularly in Europe, travellers should avoid undercooked or
poorly prepared meat products from pigs, wild boars, and deer.
Advise immunocompromised individuals and patients with chronic liver disease to avoid undercooked meat
(pork, wild boar, and venison) and shellfish, and only consume meat that has been cooked to temperatures
of at least 70ºC (158ºF).[2] [41]
Effective HEV vaccines are in development, with trials yielding promising results.[42] [43] [44] HEV vaccines
are licensed for use in China; however, they are not yet available in other countries.[1]
The European Association for the Study of the Liver (EASL) recommends that blood donor services screen
blood donors for HEV, informed by local risk assessment and cost-effectiveness studies.[2] Several countries
including the UK, France, the Netherlands, and Japan have introduced universal or targeted screening for
HEV of blood donations.[45] Blood donations are not routinely screened for HEV in the US.
Secondary prevention
Despite the similarity with hepatitis A virus, there is no role for post-exposure immunoglobulin treatment in
HEV.
MANAGEMENT
Hepatitis E Follow up
Monitoring
Monitoring
FOLLOW UP
If the patient has symptomatic acute HEV infection, monitor to identify change in clinical status that
indicates potentially severe disease (i.e., may require transplantation), particularly in pregnant women.
• Intermittent monitoring of liver enzymes and liver function tests is sufficient in patients with acute
HEV who are not taking antiviral therapy.
• Monitor coagulation parameters if the clinical picture, particularly liver function, worsens
significantly.
If the patient has chronic HEV and is on antiviral therapy, the aim of monitoring is to evaluate treatment
response and adverse effects.
Patients on ribavirin should be monitored with full blood count, chemistry panel, and HEV RNA (serum
and stool) periodically (every 4 weeks or more frequently if there are serological indications of treatment-
related adverse effects such as drop in haemoglobin/deterioration of renal function).[25]
Stop ribavirin if both serum and stool HEV RNA are negative as this indicates a sustained viral response;
note that stool HEV RNA may remain positive long after serum HEV RNA is negative, hence the
requirement for stool HEV testing to avoid relapse.
37
Complications
Complications Timeframe Likelihood

FOLLOW UP
acute liver failure /acute-on-chronic liver failure short term low
Although the definition of acute liver failure varies globally, the most commonly used definition in the US
and Europe is: an illness duration of <26 weeks in a patient with no evidence of prior liver disease or
cirrhosis with any degree of mental status alteration (encephalopathy) and coagulopathy (international
normalised ratio [INR] ≥1.5).[50]
A rare sequela of acute HEV infection and more of a concern in patients with existing chronic liver disease
(when symptoms occur in a patient with pre-existing liver disease, the term 'acute-on-chronic liver failure'
is used).[2] [11] However, acute HEV infection in pregnancy in endemic areas can lead to acute liver failure
in upwards of 20% of women.[10]
Patients who progress to acute or acute-on-chronic liver failure may present with symptoms including:[51]
[52] [53]
• Abdominal pain
• Nausea
• Vomiting
• Malaise
• Confusion, changes in personality, or somnolence (due to hepatic encephalopathy).
Patients with acute liver failure may have similar signs to those presenting with acute hepatitis infection,
but may have features of hepatic encephalopathy evident on examination. Hepatic encephalopathy
encompasses a spectrum of neurological and psychiatric changes; initial signs and symptoms may be
subtle and may include:[55]
• Asterixis
• Hypertonia
• Hyperreflexia
• Clonus
• Rigidity.
Patients with acute liver failure may also have hepatomegaly, as well as right upper quadrant tenderness.
Less commonly patients may present with features of coagulopathy.
Consider treatment with ribavirin for patients with severe acute HEV infection, patients who are at
increased risk of progression to hepatic decompensation, and those with acute-on-chronic liver failure.[2]
Case reports of ribavirin in acute HEV infection (or acute HEV infection occurring in underlying liver
disease) suggest that liver enzymes may rapidly normalise, with HEV RNA levels becoming undetectable
within days of initiation of treatment.[62]
Early recognition and diagnosis of acute liver failure is key in establishing a plan for optimal management.
Refer patients who develop signs that may be suggestive of acute liver failure to a transplant centre for
monitoring and consideration of a liver transplant.[63]
cirrhosis long term low
Chronic HEV infection, which develops almost exclusively in immunosuppressed patients, can progress
to cirrhosis if treatment is unsuccessful.[38] [72] A solid organ transplant recipient infected with HEV has
between 50% and 70% risk of developing chronic HEV infection, which can progress to cirrhosis within
several years.[38] [49]
Complications Timeframe Likelihood

Patients with chronic HEV infection who have developed cirrhosis of the liver may have stigmata of chronic
liver disease including:
FOLLOW UP
• Palmar erythema
• Spider naevi (in the distribution of the superior vena cava)
• Scleral icterus
• Ascites
• Splenomegaly
• Peripheral pitting oedema of the ankles/legs
• Loss of secondary sexual characteristics, such as loss of secondary sexual hair and testicular
atrophy in men.
Cirrhosis may lead to portal hypertension, liver failure, and hepatocellular carcinoma.
Prognosis
Acute HEV infection is clinically silent in the vast majority (up to 95%) of immunocompetent patients, and
acute liver failure is unlikely (although it may be missed in some patients as the effectiveness of HEV RNA
testing is variable).[71]
However, in pregnant women the infection can have serious consequences, with the mortality rate in this
group being approximately 25%.[10] [17] Malnourished patients and patients with underlying liver disease
may be at increased risk of decompensation after acute HEV infection.[11] A prolonged cholestatic hepatitis
can occur with acute HEV but typically resolves fully.[12]
Chronic HEV infection develops almost exclusively in immunosuppressed patients and can progress to
cirrhosis if treatment is unsuccessful.[38] [72] A solid organ transplant recipient infected with HEV has
between 50% and 70% risk of developing chronic HEV infection, which can progress to cirrhosis within
several years.[38] [49] See Complications .
39
Hepatitis E Guidelines
Diagnostic guidelines
United Kingdom
Hepatitis E: symptoms, transmission, treatment and prevention (ht tps://

www.gov.uk/government/publications/hepatitis-e-symptoms-transmission-
prevention-treatment/hepatitis-e-symptoms-transmission-treatment-and-
prevention)
Published by: Public Health England Last published: 2020
Guidelines for hepatitis E and solid organ transplantation (ht tps://bts.org.uk/

guidelines-standards)
Published by: British Transplantation society Last published: 2017
Guidelines from the expert advisory commit tee on the Safety of Blood,
Tissues and Organs (SaBTO) on measures to protect patients from acquiring
GUIDELINES
hepatitis E virus via transfusion or transplantation (ht tps://www.gov.uk/

government/publications/protecting-patients-from-get ting-hepatitis-e-
through-transfusion-or-transplantation)
Published by: SaBTO Last published: 2017
Europe
Clinical practice guidelines on hepatitis E virus infection (ht tps://

www.journal-of-hepatology.eu/article/S0168-8278(18)30155-7/fulltext)
Published by: European Association for the Study of the Liver Last published: 2018
North America
Viral hepatitis: hepatitis E (ht tps://www.cdc.gov/hepatitis/hev/index.htm)

Published by: Centers for Disease Control and Prevention Last published: 2020
Viral hepatitis: guidelines by the American Society of

Transplantation Infectious Disease Community of Practice (ht tps://
pubmed.ncbi.nlm.nih.gov/30817047)
Published by: American Society of Transplantation Last published: 2019
A guide to utilization of the microbiology laboratory for diagnosis of

infectious disease (ht tps://www.idsociety.org/practice-guideline/laboratory-
diagnosis-of-infectious-diseases)
Published by: Infectious Diseases Society of America; American Society Last published: 2018
for Microbiology
Hepatitis E Guidelines
Treatment guidelines
United Kingdom
Hepatitis E: symptoms, transmission, treatment and prevention (ht tps://

www.gov.uk/government/publications/hepatitis-e-symptoms-transmission-
prevention-treatment/hepatitis-e-symptoms-transmission-treatment-and-
prevention)
Published by: Public Health England Last published: 2020
Guidelines for hepatitis E and solid organ transplantation (ht tps://bts.org.uk/

guidelines-standards)
Published by: British Transplantation Society Last published: 2017
Europe
GUIDELINES
Clinical practice guidelines on hepatitis E virus infection (ht tps://
www.journal-of-hepatology.eu/article/S0168-8278(18)30155-7/fulltext)
Published by: European Association for the Study of the Liver Last published: 2018
North America
Viral hepatitis: hepatitis E (ht tps://www.cdc.gov/hepatitis/hev/index.htm)

Published by: Centers for Disease Control and Prevention Last published: 2020
Viral hepatitis: guidelines by the American Society of

Transplantation Infectious Disease Community of Practice (ht tps://
pubmed.ncbi.nlm.nih.gov/30817047)
Published by: American Society of Transplantation Last published: 2019
41
Hepatitis E Online resources
Online resources
1. CDC: hepatitis E information - laboratory testing requests (https://www.cdc.gov/hepatitis/hev/
labtestingrequests.htm) (external link)
ONLINE RESOURCES
Hepatitis E References
Key articles
• Centers for Disease Control and Prevention. Viral hepatitis: hepatitis E. Jun 2020 [internet publication].
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cid/article/67/6/e1/5046039) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/29955859?
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Hepatitis E Images
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IMAGES
Figure 1: Patient with jaundice
Garry Watson/Science Photo Library
51
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53
Contributors:
// Authors:
Jawad Ahmad, MD, FRCP, FAASLD

Professor of Medicine
Division of Liver Diseases, Mount Sinai Hospital, New York, NY
DISCLOSURES: JA declares that he has no competing interests.
// Peer Reviewers:
Scot t J. Cotler, MD
Professor of Medicine
Director, Division of Hepatology, Loyola University Medical Center, Maywood, IL
DISCLOSURES: SJC declares that he has no competing interests.
David John Mutimer, MBBS, MD

Professor of Clinical Hepatology
University of Birmingham, Birmingham, UK
DISCLOSURES: DJM declares that he has no competing interests.

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Straight to the point of care

Last updated: Mar 13, 2024

This topic covers HEV in adults.

undercooked meat.[1] [2]

Acute liver failure/acute-on-chronic liver failure

Acute HEV infection

Patient with jaundice

Chronic HEV infection

Acute liver failure/acute-on-chronic liver failure

Tests for HEV

Always request anti-HEV immunoglobulin M (IgM) screening in immunocompetent patients with

Characterisation of liver status

• Full blood count

• Aspartate aminotransferase (AST)

History and exam

jaundice/scleral icterus (uncommon)

Other diagnostic factors

right upper quadrant tenderness (uncommon)

abdominal pain (uncommon)

neurological manifestations (uncommon)

signs of coagulopathy (uncommon)

infected mother (for fetus)

blood/blood products transfusion

organ transplantation (if organ donor is HEV-positive)

coagulation profile may be normal or elevated

Other tests to consider

liver biopsy may demonstrate

Condition Differentiating signs / Differentiating tests

Acute viral hepatitis B • There may be no differences • Serum hepatitis B surface

Acute viral hepatitis C • There may be no differences • Serum hepatitis C virus

referenced' DILI, it was found

Acute alcoholic hepatitis • History of moderate/heavy • Aspartate aminotransferase

Condition Differentiating signs / Differentiating tests

Autoimmune hepatitis • May have an associated • There may be increased

Cytomegalovirus (CMV) • Clinical features of viral • Negative serology results

Epstein-Barr virus (EBV) • Clinical features of viral • Negative serology results

Herpes simplex virus • Clinical features of viral • Negative serology results

Wilson's disease • There may be associated • Increased 24-hour urinary

Condition Differentiating signs / Differentiating tests

Metabolic dysfunction- • Often associated • Abdominal ultrasound may

Biliary disease • May have fever, right upper • Elevated alkaline

• Liver biopsy may show

Acute fat ty liver of • Pregnant patient may • Diagnosis of exclusion

Haemolysis, elevated liver • Severe form of pre- • Reduced haemoglobin,

Condition Differentiating signs / Differentiating tests

Acute HEV infection

If hospital admission is not indicated:

Chronic HEV infection

autoimmune, and ischaemic disorders. Monitor patients closely.

Treatment algorithm overview

non-pregnant 1st supportive care

adjunct immunosuppression therapy taper

adjunct liver transplantation

pregnant 1st supportive care

adjunct liver transplantation

with solid organ 1st immunosuppression therapy taper

plus supportive care

plus supportive care