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11 Liver: FromBiochemistry toClinical Biochemistry
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101
Table 11.6
Disease Characteristics and laboratory results
Alcoholic liver disease History of alcohol abuse
Chronic hepatitis C ELISA test for the detection of anti-HCV
Primary biliary
cholangitis
Primary sclerosing
cholangitis
Autoimmune hepatitis Hypergammaglobulinemia
Chronic hepatitis B HBsAg, HBeAg, and, in some cases,
Hereditary
hemochromatosis
Wilson’s disease Family or personal history of cirrhosis at a
Non-alcoholic
steatohepatitis
ANCA anti-neutrophil cytoplasmic antibodies, anti-LKM-1 anti-liver
microsome type 1 antibodies, ALT alanine aminotransferase, AST
aspartate aminotransferase, ELISA enzyme-linked immunosorbent
assay, HBeAg antigen E of hepatitis B, HBsAg hepatitis B surface antigen, HBV hepatitis B virus, HCV hepatitis C virus, PCR polymerase
chain reaction
Common causes of liver laboratory testalterations
AST/ALT>2
antibodies
PCR for the search for viral RNA, as a
conrmation test
Anti-mitochondria antibodies
Increased IgM
Strong association with inammatory bowel
diseases
Cholangiography to establish the diagnosis
Antinucleus, antismooth muscle and ANCA
antibodies (not diagnostic)
Anti-core and anti-smooth muscle
antibodies, and ANCA in type 1, antiLKM-1in type 2
HBV-DNA
Family history of cirrhosis
Transferrin saturation and ferritin levels
should be measured, although they may be
altered for liver disease per se
Diagnosis established through genetic
investigations or liver biopsy and
calculation of the hepatic iron index
young age
Reduced circulating levels of ceruloplasmin
Increased copper content on liver biopsy
History of diabetes mellitus or metabolic
syndrome
The diagnosis could be suspected from
altered liver biochemical tests and liver
imaging tests showing liver fat inltration
that could be conrmed with biopsy
Hepatitis viruses can be classied into major and minor.
Major hepatitis viruses are hepatotropic agents, i.e., they
have a marked tropism for the liver, which is, therefore, the
primary site of their replication.
The main hepatotropic viruses that cause viral hepatitis
are:
• Hepatitis A virus (HAV)
• Hepatitis B virus (HBV)
• Hepatitis C virus (HCV)
• Hepatitis D virus (HDV)
• Hepatitis E virus (HEV)
Table 11.7 shows the main characteristics of hepatotropic
viruses.
Table 11.7
Virus A B C D E
Genome RNA DNA RNA RNA RNA
Transmission
Chronic
infection
Characteristics of hepatotropic viruses
Fecaloral or
sexual
No Yes Yes Yes No
Sexual,
parental,
or
perinatal
Sexual,
parental
Sexual,
parental
The
presence of
virus B is
mandatory
Fecaloral,
perinatal
On the other hand, minor hepatitic viruses do not have the
liver as their primarytarget, but they can reach itduring viremia, leading to hepatitis. Cytomegalovirus, Epstein–Barr
virus, Coxsackie virus, yellow fever virus, and herpesvirusare tbemain minor hepatitic viruses.
Generally, hepatitic viruses do not have a direct cytopathic action on hepatocytes, but hepatic damage maybe due
to the immune response against viruses.
Hepatitis A
Hepatitis A is caused by an RNA virus that belongs to the
Picornavirus family. HAV infection usually develops in an
acute form.
Transmission occurs mainly via the fecal-oral route, consuming contaminated food (raw or undercooked seafood,
berries, vegetables) or water, or through contact with infected
persons. In recent years, sexual transmission has also been
described. Travel to areas with high endemicityrepresents a
critical risk factor.
From a pathogenetic point of view, viral replication
occurs in the cytoplasm of hepatocytes. Liver injury is the
result of the host’s immune response to HAV.
The incubation period of hepatitis A infection averages
28 days (15–50 days). More than 70% of HAV-infected
adults present with symptomatic illness, which begins with
the sudden onset of nausea, vomiting, anorexia, fever, malaise, and abdominal pain. From a biochemical-clinical point
of view, hepatitis A is characterized by increased serum ALT,
serum bilirubin (typically ≤10 mg/dL), and alkaline phosphatase (up to 400U/L) levels. Increases in serum ALT generally precede elevations in bilirubin. Serum aminotransferase
peaks approximately 1month after exposure to the virus and
then progressively declines. Serum bilirubin concentration
usually declines within 2weeks of the peak. Other laboratory changes include increases in acute phase proteins and
markers of inammation.
Full biochemical-clinical recovery is observed within
2–3months in 85% of patients and complete recovery within
6 months in almost all patients. HAV infection does not
become chronic, and individuals cannot reinfect it.
The diagnosis of acute HAV infection is based on identifying serum anti-HAV IgM antibodies IgM is detectable
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from symptoms beginning, peaks during the convalescent
phase of the disease, and remains detectable for 3–6months.
Detection of serum IgM antibodies without clinical symptoms may reect a previous hepatitis A infection with prolonged IgM persistence, a false-positive result, or an
asymptomatic infection (which is more common in children
younger than 6years of age than in older children or adults).
Serum IgG antibodies appear early in the convalescent
phase of the disease, remain detectable for decades, and are
associated with lifelong protective immunity. Detection of
anti-HAV IgG in the absence of anti-HAV IgM indicatesprior
infection or vaccination.
Hepatitis B
Hepatitis B is caused by a DNA virus that belongs to the
Hepadnavirus family. HBV infection can develop in an acute
or chronic form. HBV represents a global public health problem. It is estimated that there are 248million HBV carriers
worldwide, of which approximately 600,000 die each year
from HBV-related liver disease. The implementation of
effective vaccination programs in many countries has
resulted in a signicant reduction in the incidence of new
hepatitis B infections. However, HBV infection remains a
signicantcause of morbidity and mortality.
HBV can be transmitted sexually, parenterally, or
perinatally.
The complete viral particle (virion) consists of:
• An outer envelope formed ofthe hepatitis B surface anti-
gen (HBsAg) and components of host-derived lipids
• A core formedof the core hepatitis B antigen (HBcAg),
the viral genome, and the polymerase
HBV also produces subviral particles in the form of laments and spheres composed only of envelope proteins.
These subviral particles do not contain the HBV genome
and, therefore, are not infectious.
The HBV genome is a circular, partially doublestranded DNA molecule, with a longer L (−) chain consisting of 3200 nucleotides and a shorter S (+) chain
varying in length from 1700 to 2800 nucleotides. Although
its size is small, the genome can encode many different
proteins (genetic economy), such as the S protein
expressed on the surface, the functional protein DNA
polymerase, which is a target of antiviral therapy, the core
antigen, and the E antigen. The core antigen represents
the structural protein of the capsid. The E antigen (HBeAg)
is generatedby a proteolytic cut of C protein.This protein, unlike the core protein, is soluble and, therefore,
released in the serum.
HBV is generally not a cytopathic virus. The pathogenesis of HBV-relatedliver disease is mainly due to immunemediated mechanisms.
Patients who progress to chronic HBV infection have an
altered immune response.
The incubation period of HBV varies from 2 to 6months.
The spectrum of clinical manifestations of HBV infection
varies in both acute and chronic forms. During the acute
phase, manifestations range from subclinical hepatitis (70%
of cases) to jaundiced hepatitis and, in some cases, fulminant
hepatitis (30% of cases). During the chronic phase, manifestations range from an asymptomatic carrier state to chronic
hepatitis, cirrhosis, and hepatocellular carcinoma. The disease may be more severe in patients co-infected with other
hepatitis viruses or underlying liver disease. Fulminant liver
failure is rare (0.1–0.5% of patients) and is thought to be due
to massive immune-mediated lysis of infected hepatocytes.
Complete eradication of HBV rarely occurs after recovery from acute infection, andT cells can controllatent infectionfor decades after clinical recovery.
The natural course of chronic HBV infection is determined by the interaction between viral replication and the
host immune response. Other factors that may play a role in
the progression of HBV-related liver disease include sex,
alcohol consumption, and concomitant infection with other
hepatitis viruses. It is important to note that not all patients
with chronic HBV infection develop chronic hepatitis. In
20% of cases, chronic hepatitis can progress to cirrhosis
within approximately 5years. Patients with cirrhosis have a
high risk of developing hepatocarcinoma.
The evaluation of the different available markers, serological or genetics, depends on the clinical presenting characteristics of the patient, or if screening is to be performed in
an asymptomatic person.
Regarding serological markers, HBV infection is characterized by particular changes in serum levels of HBV antigens and anti-HBV antibodies. Therefore, these markers are
used to dene different clinical states (Table11.8).
HBsAg andAnti-HBs
HBsAg surface antigen is the serological sign of HBV infection and the rst marker to appear. SerumHBsAg can be
detected1–10weeks after acute HBV exposure, before the
onset of clinical symptoms or ALT increase. In most cases,
HBsAg is no longer detectable after 2–4months. The persistence of HBsAg for more than 6months indicates chronic
infection. The disappearance of HBsAg is followed by the
appearance of serumantibodies against the surface antigen
(anti-HBs). In most patients, anti-HBs persist for life, thus
conferring long-term immunity. In some patients, however,
anti-HBs may not be detectable until several weeks or
months, during which neither HBsAg nor anti-HBs can be
detected. In this case, serological diagnosis can be performed
by detectingIgM antibodies against the core antigen (IgM
anti-HBc), which appear as early as 1–2 weeks after the
appearance of HBsAg.
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Table 11.8 Serological diagnosis of HBV infection
HbsAg HBeAg IgM-anti- HBc IgM and IgG anti-HBc Anti- HBs Anti- HBe HBV- DNA ALT Interpretation
Acute HBV infection
+ + + +++ Elevated Early phase
+ + Elevated Window period
+ + +
Chronic HBV infection (HBsAg positive >6months)
+ + +
+ + +
+
− − +/− +/− +/−
−
+
− −
− −
−
+ ++ Elevated Immunoactive phase,
+/−
+++ Normal or
+++ Persistently
+ liver
+/− serum
Normal Recovery phase
modestly elevated
elevated
Normal Occult HBV
Immunotolerance
phase
Immunoactive phase,
HBeAg positive
HBeAg negative
103
HBcAg andAnti-HBc
The core antigen, HBcAg, is expressed intracellularly in
infected hepatocytes; it is not detectable in serum. Antibodies
against the core antigen (anti-HBc) can be detected during
HBV infection. Specically, anti-HBc is predominantly of
the IgM class in acute infection. Anti-HBc IgM is the only
detectable marker of HBV infection during the window
period between the disappearance of HBsAg and the appearance of anti-HBs. The presence of anti-HBc IgM is usually
considered indicative of acute HBV infection. However,
anti-HBc IgM may remain detectable up to 2 years after
acute infection. In addition, anti-HBc IgM titer may increase
to detectable levels during exacerbations of chronic hepatitis
B.Common causes of acute exacerbation of chronic hepatitis B are superinfection with hepatitis D virus or hepatitis C
virus. Anti-HBc IgG persists along with anti-HBs in patients
recovering from acute hepatitis B and along with HBsAg in
patients progressing to chronic HBV infection.
HBeAg andAnti-HBe
HBeAg is a secretory protein generally considered a marker
of HBV replication and infectivity. HBeAg is usually associated with elevated serum HBV-DNA levels and higher transmission rate of HBV infection. HBeAg to anti-HBe
seroconversion occurs early in patients with acute infection,
before HBsAg to anti-HBsAg seroconversion. However,
HBeAg seroconversion may be delayed for years or decades
in patients with chronic HBV infection. In such patients, the
presence of HBeAg is usually associated with high serum
HBV-DNA levels and active liver disease.
Seroconversion from HBeAg to anti-HBe is only associated with a reduction in serum HBV-DNA and remission of
liver disease.
HBV-DNA
Qualitative and quantitative assays have been developed to
measure serumHBV-DNA to assess HBV replication. The
sensitivity limit of these assays depends on the techniques
used. Currently, most assays for the assessment of HBVDNA are based on real-time polymerase chain reaction
(PCR).
Recovery from acute hepatitis B is usually accompanied
by the disappearance of serumHBV-DNA, as determined by
hybridization analysis. However, HBV-DNA may remain
detectable in serum for many years when tested by PCR.This
observation suggests that the virus persists after “recovery”
but is controlled by the immune system. HBV-DNA levels
are also detectable in patients with HBeAg-negative chronic
hepatitis, although the levels are generally lower than in
patients with HBeAg-positive chronic hepatitis.
The main clinical utility of HBV DNA testing in patients
with chronic HBV infection is the assessment of HBV replication and eligibility for antiviral therapy. Indeed, the indications for HBV treatment are based on active liver disease and
high HBV-DNA levels. HBV-DNA suppression is also used
to assess response to antiviral treatment.
Table 11.9 shows the characteristics of HBV serological
markers.
The diagnosis of acute hepatitis B is based on identifying HBsAg and anti-HBc IgM. During the early phase of
infection, HBV replication markers, such as HBeAg and
HBV-DNA, are also detectable. Recovery is accompanied by
the disappearance of HBV -DNA, seroconversion from
HBeAg to anti-HBe, and then seroconversion from HBsAg
to anti-HBs. Rarely do patients present during the window
period when HBsAg has become negative, but anti-HBs are
not yet positive. Thiscondition is more common in patients
with fulminant hepatitis B becausevirus clearance tends to
be more rapid andanti-HBc IgM is the only marker of acute
HBV infection.
Prior HBV infection is characterized by anti-HBs and
anti-HBc IgG.Immunity to HBV infection after vaccination
is indicated only by the presence of anti-HBs.
The diagnosis of chronic HBV infection is based on the
persistence of HBsAg for more than 6 months. Additional
tests to assess HBV replication, such as HBeAg and serum
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Table 11.9 Main characteristics of serological markers of HBV
Marker Acronyms
Surface
antigen of the
hepatitis B
virus
Antigen E of
the hepatitis
B virus
Antibodies to
the E antigen
of the
hepatitis B
virus
IgM tothe
core antigen
of the
hepatitis B
virus
IgG tothe
core antigen
of the
hepatitis B
virus
Antibodies
tothe surface
antigen of the
hepatitis B
virus
HBV-DNA
(detectedby
PCR)
HBsAg It is the rst
HBeAg It is the second
Anti-Hbe Low levels can
Anti-HBc
IgM
Anti-HBc
IgG
Anti-HBs It is the last
Appearance in
serum Clinical usefulness
First diagnostic
marker to be
detectable
during the
incubation
period
marker to appear
very early after
HBsAg
be detected even
before HBeAg
disappears
Usually 2weeks
after the onset of
HBsAg and up
to 6months
before the onset
of symptoms
Levels rise early
after the onset of
anti-HBc IgM
marker to appear
in the serum
followingthe
disappearance of
HBsAg
Indicative of the
presence of the
virion
marker.
Its disappearance does
not always indicate
recovery.
Levels peak at the
same time as HBsAg
but disappear earlier.
It indicatesviral
replication, and the
patient is highly
contagious.
Seroconversion from
HBeAg to anti-HBe is
an early indicator of
recovery.
The patient is less
contagious.
Diagnostic marker of
acute HBV infection.
It has no
immunoprotective
function.
It remains detectable
throughout life.
It cannot be used to
distinguish between
acute and chronic
infection.
They are the only
antibodies that
neutralize HBV and
thus indicate
immunity.
The WHO has
established that
10mUI/L is the
threshold value to
dene a state of
immunity following
natural exposure or
vaccination.
Indicative of active
viral replication.
Frequent false
positives
HBV-DNA, should be performed to determine if the patient
is eligible for antiviral therapy. All patients with chronic
HBV infection should be monitored regularly because HBVDNA and ALT levels vary throughout the infection.
HBeAg-negative patients who have normal or low
ALTlevels or undetectable HBV-DNA are in an inactive carrier status. These patients generally have a good prognosis,
and antiviral treatment is not indicated. However, they should
undergo evaluation of ALT and HBV-DNA levels at 3-month
intervals during the rst year.
Hepatitis C
Hepatitis C is caused by a single-stranded RNA virus belonging to the Flaviviridae family. Chronic HCV infection is one
of the most common chronic liver diseases.
According to the WHO, approximately 71million people
worldwide are chronic carriers of the hepatitis C virus, and
399,000 people die each year from hepatitis C–related liver
disease. HCV is mainly transmitted by exposure to contaminated biological uids such as blood, vaginal secretions, or
semen. The infection could occur through needles and
syringes, blood transfusions, piercings, acupuncture, dental
procedures, endoscopy, and unprotected sexual intercourse.
In addition, it can be transmitted perinatally when passing
through the birth canal. Another transmission mode is
through parenteral drug use with an exchange of infected
syringes. The risk of infection is increased if there is coinfection with HIV.
HCV is not a cytopathic virus, but liver damage is
immune-mediated.
In most cases (80–90%), acute HCV infection is asymptomatic, whereas, in the remaining 10–20% of cases, the
patient has an acute infection with overt clinical symptoms
that are generally nonspecic (jaundice, nausea, dark urine,
and right upper quadrant pain). Patients with acute HCV
infection typically present with moderate-to-high ALT elevations. Approximately 50–80% of patients with acute hepatitis will develop chronic infection, while 20–50% will recover.
The mechanisms responsible for the high prevalence of viral
persistence, and therefore chronic infection, are not fully
understood. However,it is likely that both viral and host factors, such as the age of acquisition of infection (acquisition at
age>50years is associated with a higher risk of infection),
co-infections with other liver viruses or HIV, alterations in
immune status, sex (women are at lower risk), ethnicity
(Caucasians are at higher risk), and the presence of other
causes of liver disease such as alcohol consumption may
contribute.
In 20% of cases, chronic hepatitis progresses to livercirrhosis, characterized by a continuous deposition of connective tissue, which alters the normal architecture of the organ,
leading to a progressive loss of function to death; in 1–4% of
cases, there is the development of hepatocarcinoma.
Figure11.3 showsthe natural history of HCV infection.
By convention, acute HCV infection refers to the rst
6months of infection following presumed exposure to the
virus. HCV infection is estimated to account for 15% of
symptomatic cases of acute hepatitis, whereas most patients
with acute HCV are undetected. This is mainly
because patients with acute HCV infection are typically
asymptomatic.
ALT levels are often greater than 10–20 times the
upperreference limit in patients with acute HCV infection but exhibit high variability. Furthermore, during
Acute HCV infection
Spontaneous
cirrhosis
Hepatocellular
carcinoma
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11 Liver: FromBiochemistry toClinical Biochemistry
20 – 50% 50 – 80%
clearance
30% 30%40%
Chronic
stable
infection
Fig. 11.3 Natural history of HCV infection. (Copyright EDISES 2021.
Reproduced with permission)
Chronic infection
Slow
progression to
fibrosis
>20 years
Compensated cirrhosis
≈ 4%/year ≈ 1.5%/year
Decompensated
Rapid
progression to
fibrosis
<20 years
acute infection, ALT levels can vary widely within short
intervals, in contrast to a chronic infection, during which
they are often elevated but relatively stable over time.
Among patients who develop symptoms, aminotransferases rise shortly before the onset of clinical symptoms
and usually before anti-HCV antibodies are detectable.
However, because levels often fluctuate and may even
normalize, not all patients will have elevated aminotransferase levels at the presentationtime. Patients with acute
HCV infection may also have elevated total bilirubin levels (>3mg/dL).
The detection of HCV-RNA by PCR in subjects with
undetectable HCV antibodies, which subsequently become
detectable within 12weeks, is generally indicative of acute
HCV infection. Alternatively, the nding of HCV antibodies
and HCV-RNA in a patient with negative tests in the preceding 6 months is indicative of acute HCV infection. In the
absence of such documentation, the distinction between
acute HCV infection and newly discovered chronic infection
is not straightforward, as patients in both settings may have
detectable HCV-RNA, anti-HCV antibodies, and elevated
serum ALTlevels.
Serum HCV-RNA is detectable by PCR within a few days
to 8weeks after exposure to the virus.
Enzyme-linked immunosorbent assays (ELISAs) that
detect HCV antibodies become positive as early as 8weeks
after exposure, and most patients seroconvert 2–6 months
105
after exposure. HCV antibody positivity does not allow differential diagnosis between acute and chronic infection.
Figure 11.4 illustrates the algorithm for the valuation of
acute HCV infection in a patient with acute hepatitis (elevated ALT and/or jaundice). For a patient presenting following known exposure to HCV, rst tests for HCV-RNA,
anti-HCV antibodies, and ALT are performed to establish
baseline HCV status (Fig. 11.4). Within 1–2days after an
exposure, a patient without a previous infection should test
negative for HCV-RNA and anti-HCV antibodies, with nominal ALT values. Figure11.5 shows the algorithm for assessing acute HCV infection in a patient with recent exposure to
the virus.
Acute HCV infection can resolve but, in most cases, will
become chronic. Chronic HCV infection progresses slowly
and may not result in clinically evident liver disease.
Approximately 5–30% of chronically infected persons
develop cirrhosis within 20–30years. Patients who develop
cirrhosis are at risk for complications, such as varicose
bleeding, ascites and encephalopathy, and hepatocellular
carcinoma, although many patients with compensated cirrhosis remain stable for years. Patients with chronic infection have wide variability in serum ALT levels over time. Up
to one-third of patients have normal ALT levels; mild
increases are usually observed in about two-thirds of patients,
and only about 25% have a serum ALT concentration greater
than two times the upper reference limit. Generally, however,
there is little correlation between aminotransferase levels
and liver histology. During chronic HCV infection (i.e., after
the acute phase), HCV viral levels remain constant, although
signicant uctuations may occur. Useful laboratory tests to
identify cirrhosis in HCV-infected patients include serum
bilirubin concentration (increased), hypoalbuminemia, or
platelet count (decreased). Serum alpha-fetoprotein (AFP)
concentration may be slightly increased in chronic HCV
infection and does not necessarily imply the presence of
hepatocellular carcinoma or cirrhosis; up to 43% of patients
with cirrhosis without hepatocellular carcinoma have a
serum AFP between 10 and 100ng/mL. However, an elevated serum AFP concentration requires liver imaging to rule
out hepatocellular carcinoma.
Hepatitis D
Hepatitis D is caused by a defective RNA virus, the hepatitis
D virus (HDV), also called delta virus; it is dened as defective because, although it can replicate on its own, it requires
the simultaneous presence of HBV for the assembly and
secretion of complete virions. Thus, HDV cannotinfect a
cell on its own but requires the simultaneous presence of
HBV infection. Consequently, people with hepatitis D are
always infected with HDV and HBV. Due to incompletely
understood interference mechanisms, HBV replication is
suppressed in most HDV-infected individuals.
106
Biochemical and clinical signs/symptoms of acute hepatitis
Probab
to confirm seroconversion
V
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HCV-RNA (PCR) and Ab-HCV detection
Has an HCV-RNA or Ab-HCV
negative serum sample been
documented in the previous
No Ye s
Is there a high risk
of recent HCV
exposure?
No Ye s
le chronic
HCV infection
HCV-RNA +
HCV-Ab +
HCV
infection (acute or
chronic)
6 months?
Probable acute
HCV infection
Monitor HCV-RNA to assess clearance.
If initially negative, check Ab-HCV at 12 weeks
HCV-RNA +
HCV-Ab –
Acute HCV infection
HCV-RNA –
HCV-Ab +
Re-check
HCV-RNA in
12 weeks
HCV-RNA+ HCV-RNA–
Past HCV infection
HCV-RNA –
Unlikely HC
HCV-Ab –
infection
Fig. 11.4 Diagnostic algorithm for acute HCV infection in a patient with clinical symptoms. (Copyright EDISES 2021. Reproduced with
permission)
Vaccination against hepatitis B has contributed to the pro-
gressive decrease inthe incidence of HBV over the past 30years.
HDV has a very high replication rate in hepatocytes.
This virus can give rise to two types of infection.
• Acute HDV superinfection: occurs in a patient who was
already infected with HBV and became overinfected with
the hepatitis D virus. HDV superinfection of a chronic
HBsAg carrier may occur as severe acute hepatitis in a
previously unrecognized HBV carrier or as an exacerbation of preexisting chronic hepatitis B. Progression to
chronic HDV infection occurs in almost all patients.
However, HBV replication is usually suppressed by HDV.
• Acute HBV/HDV co-infection: occurs in a patient who is
simultaneously infected with both viruses. Co-infection
The detailed mechanisms by which HDV induces liver
damage are unknown. However, the pathogenesis of hepatitis D–related liver disease appears to depend on the interaction between host-associated factors, such as the immune
response, and virus-associated factors, such as HBV genotype and HBV replication level.
HDV is thought to cause direct cytopathic injury during
acute infection, while immune-mediated damage predominates during chronic infection.
Hepatitis D can only be diagnosed in HBsAg-positive
patients.
In HDV-infected individuals, the timing of onset and
circulating levels of HDV-RNA, HDAg, and anti-HDV
allows discrimination between three different clinical
conditions:
of HBV and HDV causes acute hepatitis B+D, which is
clinically indistinguishable from classical acute hepatitis
B and is usually transient and self-limited; the risk of
chronicity is low.
• Acute HBV/HDV co-infection
• Acute HDV superinfection in a chronic HBV carrier
• Chronic HDV infection.
Exposure to HCV
P
No new HCV infection
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Detection of HCV-RNA (PCR) and Ab-HCV within 48 hours
107
HCV-RNA +
HCV-Ab +
ast HCV infection,
probably chronic
HCV-RNA +
HCV-Ab –
Acute HCV infection
HCV-RNA –
HCV-Ab +
Past infection
resolved, but at risk
of reinfection
Re-check HCV-RNA at 4 weeks
HCV-RNA +
Retest HCV-RNA and Ab-HCV
HCV-RNA + or
seroconversion
HCV-RNA –
(if previously negative) at
12–16 weeks
and no seroconversion
previously negative) at
HCV-RNA –
HCV-Ab –
HCV infection unlikely
HCV-RNA -
Retest HCV-RNA
and Ab-HCV (if
6 months
Monitor HCV-RNA to assess clearance.
Fig. 11.5 Diagnostic algorithm for acute HCV infection in a patient with recent exposure to the virus. (Copyright EDISES 2021. Reproduced with
permission)
Due to the dependence of HDV on HBV, the presence of
HBsAg is required to diagnose HDV infection. The additional presence of anti-HBc IgM is required acute HBV/
HDV co-infection (Table11.10).
Serum HDAg can be detected by enzyme-linked immunosorbent assay (EIA) or radioimmunoassay (RIA) on
microplates.
In acute HDV infection, serum HDAg appears early but
has a very short half-life and may escape detection if repeated
testing is not performed. In chronic HDV infection, antiHDV is present at a high titer.
HDV RNA can be detected in serum by Reverse
Transcriptase-PCR (RT-PCR) (Table11.10).
If initially negative, check Ab-HCV at 12 weeks
to confirm seroconversion
HCV-RNA - and
no seroconversion
Total HDV antibodies (IgM and IgG) usually appear after
4weeks of acute HDV infection. Consequently, their clinical
value is limited unless repeat testing is performed. However,
a well-documented anti-HDV seroconversion may be the
only way to diagnose acute HDV infection in the absence of
other markers of HDV infection.
High titer anti-HDV IgG is present in chronic HDV infection and correlates well with ongoing HDV replication.
Itmay help differentiate between recent and past HDV infection. Anti-HDV IgM is transient and delayed if the course of
acute hepatitis D is self-limited but maybe the only serum
marker of acute HDV infection. The differential diagnosis
between HBV/HDV co-infection and HDV superinfection in
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Table 11.10 Diagnostic marker of HDV hepatitis
Acute
Diagnostic
marker
HBsAg Positive Positive Positive
Anti-HBc IgM Positive Negative Negative
HDAg Early and
HDV-RNA Early, transient
Total anti-HDV Late, low title Titer
Anti-HDV IgM Transient but it
co-infection
HBV/HDV
short-lived
but lasts longer
than HDAg
could be the only
marker
HDV
superinfection
Early and
transient
Early and
persistent
progressively
increases
Titer rises
rapidly and
persists
HDV chronic
infection
Undetectable
Usually,
positive
High titer
Variable titer,
usually high
an HBV carrier is mainly based on the detection of high titer
anti-HBc IgM in patients with co-infection.
Anti-HDV IgM is present at high titers during chronic
HDV infection, and titers correlate with the HDV replicationrate and the severity of the liver disease. Anti-HDV IgM
gradually disappears from serum in patients who have remission after interferon therapy and after liver transplantation.
Hepatitis E
Hepatitis E is caused by the hepatitis E virus, which belongs
to the family Hepeviridae and consists of a linear single helix
RNA genome.
Transmission of HEV can occur through contaminated
food and water, blood transfusions, and via the perinatal
route. Person-to-person transmission is quite rare.
The pathogenesis of hepatitis E is poorly understood. The
virus is not cytopathic and, therefore, the liver injury could
be immune-mediated by cytotoxic T cells and natural killer
(NK) cells.
HEV generally causes acute self-limited infection,
although acute liver failure may develop in a small percentage of patients. The incubation period of HEV infection
ranges from 15 to 60days. Most patients with acute HEV
infection are asymptomatic or mildly symptomatic. In symptomatic patients, jaundice is usually accompanied by malaise, anorexia, nausea, vomiting, abdominal pain, fever, and
hepatomegaly. Other less common features include diarrhea,
arthralgia, pruritus, and urticarial rash.
Laboratory ndings include elevated serum concentrations of bilirubin and ALT. Symptoms coincide with an
abrupt increase in serum ALT levels. In immunocompromised patients, the development of chronic hepatitis leads to
inammation and progressive brosis, which can lead to cirrhosis. Most patients who acquire HEV spontaneously eliminate the virus. However, patients may develop complications,
such as acute liver failure, cholestatic hepatitis, or chronic
HEV infection. Chronic HEV infection occurs almost exclu-
sively in immunosuppressed patients (e.g., patients with HIV
infection after solid organ or bone marrow transplantation).
The diagnosis of HEV hepatitis should be considered in
patients presenting with acute or chronic hepatitis thatother
causes cannot explain. The lack of a standardized assay complicates the diagnosis of acute HEV infection. Several EIA
kits have been developed that exhibit high variability in test
performance; both false positives and negatives are common
with available tests.
The timing of the appearance of HEV markers is important for interpreting serologic test results in the context of
acute hepatitis.
Anti-HeV IgM appears during the early phase of clinical
disease and disappears rapidly within 4–5months. Anti-HeV
IgG appears shortly after IgM, and the titer increases
throughout the acute phase until the convalescent phase. It is
unclear how long anti-HEV IgG antibodies persist. HEVRNA can be detected in the stool approximately 1 week
before the onset of illness and may persist up to 2 weeks
later. In serum, HEV-RNA can be detected 2–6weeks after
infection and may persist for 2–4weeks in those who resolve
the acute infection. Although HEV viremia is short-lived in
most patients with acute infection, it may persist for years in
those who develop chronic infection.
In general, the rst test to evaluate the presence of acute
HEV infection should be the detection of anti-HEV
IgM.Conrmatory testing should be performed if this test is
positive, as no single EIA method achieves high specicity.
Conrmatory testing may include evaluating anti-HEV IgM
by a different method, evaluating an increased anti-HEV IgG
titer (>5 times over 2 weeks), or detecting HEV-RNA in
serum or stool.If the initial test is negative and there is still a
high suspicion of HEV infection, the test should be repeated,
preferably in conjunction with the detection of HEV-RNA.
In patients with suspected chronic HEV infection, detecting serum HEV-RNA is the cornerstone of diagnosis. Chronic
HEV infection is dened by identifying HEV-RNA in serum
or stool over more than 6months. The HEV IgG antibody
test is of limited utility in the diagnosis of chronic HEV
infection. Indeed, anti-HEV IgG is a marker of HEV exposure, whether recent or previous. In addition, the reduction of
anti-HEV IgG titer overtime could adversely affect its sensitivity to detect past infection.
Iatrogenic Hepatitis
Many drugs, both prescription andover-the-counter, as well
as herbal products, can have hepatotoxic effects through various mechanisms. Drug-induced liver injury accounts for
approximately 10% of all causes of acute hepatitis and is one
of the most frequent reasons for drug withdrawals.
Drug-induced liver damage has an estimated annual incidence of about 10–15 cases per 10,000–100,000 people on
prescription.
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109
Several risk factors have been associated with the development of hepatic drug injury. In general, adults are at higher
risk than children (with the notable exception of valproic
acid damage, which is more common in children); women
may be more susceptible than men, which may be due in part
to their generally smaller body size; alcohol abuse and poor
nutrition in some cases are predisposing factors, as in the
case of acetaminophen.
More than 1000 drugs and herbal products are known to
induce liver damage, and the list continues to grow. The
National Institutes of Health maintains a research database
of drugs, medications, herbal products, and dietary supplements associated with liver damage. The drug most implicated in acute liver injury is acetaminophen, followed by
antibiotics; in particular, amoxicillin-clavulanate is one of
the most reported causes of hepatopathy.
The liver is responsible for the selective absorption, concentration, metabolism, and excretion of most drugs and toxins introduced into the body. While some drugs can directly
cause hepatotoxicity, their metabolites generally result in
liver damage. Drugs are processed by a wide variety of
enzymes, and each has its own specic biotransformation
pathway involving one or more enzyme systems.
In general, factors that alter the activity of an enzyme
have the potential to increase the toxicity of a compound (by
reducing its conversion to nontoxic metabolites or increasing
its conversion to toxic metabolites) or decrease its therapeutic efcacy (e.g., by increasing the rate of inactivation of the
active compound).
Several factors can alter the activity of drug-metabolizing
enzymes and, consequently, affect drug metabolism, contributing to hepatotoxicity:
• Genetics: Several polymorphisms are known in the genes
encoding for enzymes involved in drug metabolism that
may contribute to a reduction or excess of metabolization
of a compound.
• Alcohol intake: Chronic alcohol ingestion increases the
activity of certain enzymes.
• Nutrition: Some foods can alter the activity of specic
enzymes.
• Presence of other drugs: The concomitant use of two or
more drugs is one of the most important factors affecting
the components of the cytochrome system and, conse-
quently, drug metabolism.
• Patient demographics: It has been reported that a general
decrease in cytochrome activity develops with increasing
age. Infants, on the other hand, present considerable
immaturity in the enzymatic kit, which develops over
time. Finally, women aremore susceptible to hepatic drug
injury than men. Ethnic differences in the presentation
and prognosis of drug-related liver injury have also been
reported. African-American subjects areat greater risk for
severe skin reactions and severe hepatic injury than
Caucasian subjects.
• Underlying liver disease: Both acute and chronic liver
disease have a variable effect on the metabolism of many
drugs. Enzyme activities are generally reduced with
increasing disease severity.
• Dose: Hepatic injury from intrinsic hepatotoxins is clearly
dose-related.
Drug-induced liver injury is a complex process involving
the drug, its metabolites, and the host immune system. Most
of the effects of hepatotoxic drugs result in necrosis or apoptosis of hepatocytes. However, some drugs predominantly
damage bile ducts, export proteins, andcanaliculi (cholestasis), vascular endothelial cells (sinusoidal obstruction syndrome), or stellate cells. Thus, drug-induced liver damage
may have the features of hepatitis, cholestasis, or mixed; the
differential diagnosis is made based on the biochemicalclinical picture.
The acute presentation of drug-induced liver damage var-
ies from a mild alteration of the hepatic biochemical-clinical
prole without symptoms or with nonspecic symptoms
such as malaise, mild fever, anorexia, nausea, vomiting, right
upper quadrant pain, jaundice, or dark urine, to cholestasis
with pruritus, acute hepatitis with jaundice reminiscent of
viral hepatitis, and acute liver failure. Chronic liver damage
manifests like other chronic liver diseases, such as autoimmune hepatitis, primary biliary cirrhosis, or sclerosing cholangitis. In some patients, chronic drug-induced damage
progresses to cirrhosis.
In most cases, patients are asymptomatic, and laboratory
testsreveal the injury. Diagnosis is based on obtaining a thorough history and laboratory investigations to rule out other
potential causes of liver damage. Patients with hepatocellular
damage will have a marked increase in aminotransferase levels (>25 times the upper limit of normal). In contrast,patients
with cholestatic damage will predominantly have an increase
in alkaline phosphatase. Serum bilirubin may be elevated in
both cases.
If there is evidence of cholestasis, imaging to rule out bili-
ary obstruction is also indicated. If testing for alternative
causes of liver damage is negative and the patient has been
exposed to a drug associated with liver damage, a liver
biopsy is generally not performed. However, a liver biopsy
should be performed if the diagnosis remains uncertain
(especiallyin the context of acute liver failure) or if there is
clinical evidence of chronic hepatopathy.
There are no specic circulating biomarkers that can reli-
ably identify a drug as a cause of liver injury.
Key elements for attributing liver injury to a drug include:
• Exposure to the drug prior to the onset of liver injury
(although the latency period is highly variable)
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M. Ciaccio et al.
• Exclusion of underlying liver disease
• Improvement in liver injury after discontinuation of the
drug
• Rapid and severe relapse with repeated exposure to the
drug
• Assumption of a drug already associated with possible
liver damage.
Steatosis, Fibrosis, andCirrhosis
Nonalcoholic Hepatic Steatosis
Nonalcoholic fatty liver steatosis (NAFL) is dened by the
accumulation of lipids in the hepatocyte greater than 5% in
subjects in whom chronic alcohol abuse or other conditions
that may generate hepatic steatosis are excluded
(Table11.11).
Steatosis, with or without inammation, is often associ-
ated with brosis and may progress to cirrhosis. Generally,
benign NAFL can be distinguished from Nonalcoholic
Steatohepatits (NASH) with or without brosis, which may
progress to cirrhosis, liver failure, and hepatocarcinoma.
There is no signicant evidence of inammation in hepatic
steatosis, whereas, in steatohepatitis, steatosis is associated
with hepatic inammation, which may be indistinguishable
from alcoholic steatohepatitis on histological examination.
Nonalcoholic Fatty Liver Disease (NAFLD), which
includes the entire spectrum of nonalcoholic liver diseases
ranging from steatosis to steatohepatitis andcirrhosis, is the
most frequent chronic liver disease in Western countries,
where its main risk factors– central obesity, type 2 diabetes
mellitus, dyslipidemia, and metabolic syndrome– show an
increasing prevalence. In Europe, the incidence of NAFLD
Table 11.11 Main causes of steatosis
Macrovesicular
steatosis
Microvescicular
steatosis
Alcoholism
Hepatitis C (genotype 3)
Wilson’s disease
Lipodystrophy
Undernutrition
Parenteral nutrition
Abetalipoproteinemia
Use of drugs such as mipomersen, lomitapide,
amiodarone, methotrexate, tamoxifen,
corticosteroids
Reye’s syndrome
Use of drugs such as valproate, andantiretroviral agents
Acute fatty liver disease of pregnancy
HELLP syndrome
Congenital defects of metabolism (lecithincholesterol deciency acyltransferase,
cholesterol ester storage disease, Wolman
syndrome)
in the adult population is 20–30% but reaches up to 70%
when considering diabetic subjects.
NAFLD is most frequently diagnosed during the fth or
sixth decade of life, while the association with sex has not
yet been claried since some studies report it to be more frequent in men andothers in women. Patients with NAFLD,
especially the subgroup with NASH, frequently present one
or more components of the metabolic syndrome, particularlycentral obesity, arterial hypertension, dyslipidemia, and
insulin resistance. However, the association between NAFLD
and cardiovascular disease appears independent of the metabolic syndrome. Other conditions associated with NAFLD
are cystic ovary syndrome, hypothyroidism, obstructive
sleep apnea, hypopituitarism, and hypogonadism.
The pathogenesis of NAFLD has not yet been elucidated
in many aspects, but insulin resistance would seem to play an
important role. It has also been proposed that a second insult,
such as oxidative damage, is required for the inammatory
necrosis typical of steatohepatitis. Intrahepatic iron accumulation, leptin, deciency of antioxidant agents, and an imbalance in the intestinal microbiota have been proposed as
potential pro-oxidant elements against the hepatocyte.
Most patients with NAFLD are asymptomatic. Fatigue,
generalized malaise, and diffuse right upper abdominal pain
may occasionally be observed in patients with NASH.Patients
often come to the physician’s attention for the occasional
nding of increased serum transaminase values or steatohepatitis on abdominal imaging. On physical examination,
patients with NAFLD may present with hepatomegaly
caused by fatty liverinltration, which is sometimes the rst
sign. However, the presence of hepatomegaly is highly variable in these patients.
From a biochemical-clinical point of view, patients with
NAFLD have a slight-to-moderate increase in ALT.
However, normal transaminases should not exclude
NAFLD. When elevated, transaminases are two to ve
times the upper reference limit, with an AST/ALT ratio of
less than 1. The increase in transaminases does not predict
the severity of inammation or brosis, just as transaminase values in the normal range do not rule out clinically
relevant diseases. Alkaline phosphatase may exceed two to
three times the upper reference limit. Albuminemia and
bilirubinemia are typically in the normal range but may
show variation in patients in whom the disease has progressed to cirrhosis. Similarly, prolonged prothrombin
time, thrombocytopenia, and neutropenia are observed in
patients with cirrhosis.
Patients with NAFLD may present with increased serum
ferritin or transferrin saturation. Ferritin values greater than
1.5 times the upper reference limit have been shown to be
associated with greater disease severity and more advanced
liver brosis. Patients with NAFLD may also havepositivity
for antinuclear autoantibodies (ANA) and antismooth mus-
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