Ministry of education and science of Ukraine

V.N. Karazin Kharkiv National University

DIFFERENTIAL DIAGNOSIS AND TREATMENT

OF VIRAL HEPATITIS IN CHILDREN

METHODICAL RECOMMENDATIONS
for students 5th and 6th course of medical faculty

Kharkiv ‒ 2018
 УДК 616.36-002-022.7-079.4-08-053.2(072)
М 54

Reviewers:
L.A. Strashok– Professor of Department of Adolescent medicine of the
Kharkiv Medical Academy of Postgraduate Education, Doctor of Medicine
N.S. Shevchenko – Head of Department of Pediatrics №2 of V.N.Karazin
Kharkiv National University, Doctor of Medicine

Approved to the print by the decision of Scientific Council

V.N. Karazin Kharkiv National University
(protocol № from )

Rzhevska O.O.
M54 Differential diagnosis and treatment of viral hepatitis in children:
methodical recommendations / Compliers: O.O. Rzhevska, T.V. Zimnytska.– Kharkiv :
V.N. Karazin Kharkiv National University, 2018. – 28 p.

УДК 616.36-002-022.7-079.4-08-053.2(072)

© V.N. Karazin Kharkiv National University, 2018

© O.O.Rzhevska, T.V.Zimnytska, compliers, 2108
© Donchik I. M., design of a cover, 2018

2
 CONTENTS

LIST OF ACRONYMS......................................................................
INTRODUCTION………………………………………………..…
INFECTIOUS VIRAL HEPATITIS……………………………..…
VIRAL HEPATITIS A……………………………………….….….
VIRAL HEPATITIS E……………………………………….……..
VIRAL HEPATITIS B……………………………………….……..
VIRAL HEPATITIS C……………………………………….……..
VIRAL HEPATITIS D……………………………………….….….
DIFFERENTIAL DIAGNOSIS OF VIRALHEPATITIS…….…....
DIAGNOSIS OF VIRAL HEPATITIS………………………….….
TREATMENT OF VIRAL HEPATITIS…………………….……..
PREVENTION OF VIRAL HEPATITIS…………………...……...
QUESTIONS FOR SELF-CONTROL…………………….…..…...
TESTS……………………………………..………………..………
REFERENCE…………………………………………….…………

3
 LIST OF ACRONYMS

Ab Antibody
Ag Antigene
ALP Alkaline phosphatase
ALT Alanine aminotransferase
AST Aspartate aminotransferase
CBC Complete blood count
DIC- Disseminated intravascular coagulation syndrome
syndrom Deoxyribonucleic acid
DNA γ-glutamil transpeptidase
GGTP Polymerase chain reaction
PCR Prothrombin time
PT Ribonucleic acid
RNA Viral hepatitis A
VAH Viral hepatitis B
VBH Viral hepatitis C
VCH Viral hepatitis D
VDH Viral hepatitis E
VEH Viral hepatitis F
VFH Viral hepatitis G
VGH Viral hepatitis TTV
VTTVH Ultraviolet irradiation
UVI

4
 INTRODUCTION

Viral hepatitis has emerged as a major public health problem throughout

the world affecting several hundreds of millions of people. Viral hepatitis is a
cause of considerable morbidity and mortality in the human population, both
from acute infection and chronic sequelae which include, in the case of hepatitis
B, C and D, chronic active hepatitis and cirrhosis. Hepatocellular carcinoma
which is one of the ten most common cancers worldwide, is closely associated
with hepatitis B, and at least in some regions of the world with hepatitis
C virus.
In May 2016, during the 69th Session of the World Health Assembly,
the Global Health Strategy for Viral Hepatitis 2016‒2021 was adopted.
The purpose of this Strategy is to resolutely combat the pandemic of hepatitis
and eradicate this virus in the world by 2030. Ukraine, together with other
countries, supports the adopted this Global Strategy, since the topic of viral
hepatitis, including children, is extremely important for our country.

5
 INFECTIOUS (VIRAL) HEPATITIS

Infectious (viral) hepatitis is group of infectious diseases that are caused

by primary hepatotropic viruses, with a fecal-oral and hematologic transmission
mechanism that are characterized by a predominant liver injury.
Classification of viral hepatitis (Timchenko V., 2012)
I. By the etiological agent
Hepatitis A ‒ VAH
Hepatitis B ‒ VBH
Hepatitis C ‒ VCH
Hepatitis D ‒ VDH
Hepatitis Е ‒ VEH
Hepatitis F – VFH
Hepatitis G ‒ VGH
Hepatitis TTV – VTTVH
II. By the mechanism of transmission
1) with fecal-oral (VAH, VEH)
2) with hemocontagious (VBH, VCH, VDH, VEH, VFH, VGH)
III. By the form of the disease
1) typical (cholestatic and cytolitic hepatitis)
periods of the disease:
- incubation
- pre-icteric
- icteric
- post-icteric
- reconvalescence
2) atypical
- anicteric form
- asymphtomatic form
- subclinical (latent) form
- worn form
IV. By severity
- mild form
- moderate form
- severe form
- malignant (fulminant) form (VBH, VCH, VEH)
Criteria of severity 1) on the severity of clinical symptoms;
2) for the expressiveness of changes in biochemical parameters
V. By the duration
- acute (1‒3 months)
- prolonged (4‒6 months)
- chronic (VBH, VCH) ‒ more than 6 months
6
VI. By the nature of the duration:
1) uncomplicated
2) complicated: - with clinical and biochemical exacerbations
- with complications
- with accession of secondary infection

VIRAL HEPATITIS А

Viral hepatitis A is an acute, cyclic disease, caused by RNA-containing

enterovirus, with the fecal-oral
mechanism of transmission, characterized by the brief symptoms of intoxi-
cation, rapid dynamics of clinical and biochemical symptomatic, with
a favorable end.
Historical information: First an idea about infectious
nature of "catarrhal icterus" is outspoken by Botkin (1888); since this time
this disease got the name "Botkin disease" for a long time. In 1947 Mac-Kolum
offered a term "hepatitis A".
Etiology
Hepatitis A virus was isolated by Purcell in 1973. It is RNA-containing
virus 27 nanometers in diameter, a member of the Picornavirus family. Related
to enteroviruses, formerly known as Enterovirus 72, now put it its own family –
heptoviridae. The virions shallow, simply arranged, genome doesn`t have a core
structure. Hepatitis A virus has one antigen ‒ HAV Ag. Steady in an
environment and to many disinfectants (chloroform), 85 degrees are fully
inactivated at a temperature and autoclaving. At an ultraviolet irradiation
a causative agent perishes through 60 p. In presence a chlorine in the
concentration of a 0,5‒1 ml/л, at рН 7,0 30 mines survive and more,
that determines his ability to be saved set time in the chlorinated plumbing.
Epidemiology
A reservoir and source of infection are a sick man with any displays of
illness (by icteric, anicteric, asymptomatic and innaparant forms). Dangerous
for surrounding since the 2th week of latent period of illness; a peak of
selection by virus is the first week of illness. Contagiousness of patient with
appearance of icterus diminishes considerably. Chronic carriage of virus it
is not set.
A mechanism of transmission is fecal-oral. Natural receptivity is high.
Children are most receptive from 2 to 14 years old. The asymptomatic forms of
illness form less tense immunity. After the carried infection proof tense
immunity is produced. Basic epidemiology signs: Viral hepatitis And general
distribution, recurrence (through years), fall-winter. Hepatitis A causes only

7
acute hepatitis, rarely fulminant hepatitis (< 1% cases). Humans appear to be
the only reservoir for this virus.
The transmission HAV occurs by person-to-person contact, by the fecal-
oral route. Common-source foodborne and waterborne outbreaks have occurred
Stages of pathogenesis
1. Introduction of causative agent enteric phase
2. Regional lymphadenitis
3. Primary generalization of infection
4. Hepatogenic phase: (a) unstable localization and secondary generalization of
infection, (b) immunogenesis and liberation of organism from causative agent.
Syndrome of cytolysis is characterized by violation of integrity of
membrane of hepatocytes and exit in free circulation of hepatic transferasis
(ALT, formerly serum glutamic-pyruvic transaminase) and aspartate
aminotransferase (AST, formerly serum glutamic-oxaloacetic transaminase).
Monitor AST/ALT. There is usually slow improvement in the levels over
several weeks, but AST/ALT levels lag behind the serum bilirubin level, which
tends to normalize first. Rapidly falling aminotransferase levels may predict a
poor outcome, particularly if their decline occurs in conjunction with a rising
bilirubin level and a prolonged prothrombin time (PT); this combination of
findings usually indicates that massive hepatic injury has occurred.
Syndrome of cholestasis ‒ characterized by violation of forming and out
flow of bile with the accumulation of her constituents in blood ‒ cholesterol,
alkaline fosphatasis, bilious acids, Burshtein`s test. The clinical symptom of
cholestasia is an itch of skin. Cholestasis, defined by elevated serum conjugated
bilirubin levels, results from abnormal biliary flow at the canalicular and
cellular level due to hepatocyte damage and inflammatory mediators. Elevation
of serum alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGTP),
urobilinogen. Improvement tends to parallel the acute hepatitis phase.
Syndrome of hepatic-cellular insufficiency by the characterized decline of
functional activity of hepatocytes, that shows up the decline of albumen,
Fibrinogenum, factors of hemopexis.
Excretory-biliary syndrome is characterized by violation of egestion of
bilirubin by the damaged hepatocytes. It`s clinically characterized by an icterus,
color change of excrements.
Mesenchymal-inflammatory syndrome is expression of activating of
immunocompetent cells. A syndrome is reflected by a thymol test. Clinically
shows up a fervescence, jumboizing of spleen, hypergammaglobulinemia.
Clinical manifestation virus hepatitis A
Typical (icteric) form includes following periods:
1. Latent period: (15‒30 days) – patients are asymptomatic during this
phase. Laboratory studies demonstrate serological and enzyme markers
of hepatitis.
8
2. Pre-icteric period (3‒8 days) is characterized with
- Dyspeptic syndrome. Patients have nausea, vomiting arising up more often
after eating. Bitter taste in to the mouth, belching, diarrhea are possible.
- “Flu like syndrome“ is characterized by a fever (from subfebrilical to the high
numbers), weakness, muscular pains, development of catarrhal symptoms ‒
cough, sneeze, stuffiness in a nose, pharyngalgia or persecutions.
- Asthenovegetative syndrome is characterized by development of general
weakness, loss of appetite, irritability, by an anxiety etc.
- Abdominal syndrome is characterized by the dull, pain in right
hypochondrium.
3. Icteric period: with appearance of icterus feel at the half of patients it is
possible to consider as satisfactory, at other as middle form 2‒3 days.
The ochrodermia of sclera, and then facial, trunk, hard and soft palate, later ‒
extremities skins, appears at the beginning. An icterus grows quickly, in the
flow of 1‒2 days, turns yellow as though for a 1 night. On height of icterus of
size of liver maximally increased in size. The edges of liver are close-settled,
rounded, sickly at palpation. An increase of liver is even, but the left stake is
more often increased in size. A spleen was increased in size at the symptoms of
intoxication diminish appearance of icterus (an icterus "drives" away illness).
On 7‒10 day an icterus begins to diminish, it is accompanied by complete
disappearance of symptoms of intoxication, improvement of appetite. Bilious
pigments disappear in urine, an excrement is painted.
4. Post-icteric period ‒ characterized by normalization of sizes of liver, renewal
of her function. The state of child is fully satisfactory. May develop right upper
quadrant pain with hepatomegaly and splenomegaly (20 %). May appear
tranciently for few days.
5. Convalescent period. Sometimes children grumble about rapid fatigue ability
after physical activity, stomach-ache, sometimes there is a jumboizing of liver.
Duration of period is about 2‒3 months.
Cholestatic form. Syndrome of mechanical jaundice. Jaundice long 30‒40
days with greenish or saffron skin color. Itching of the skin (sometimes
predominates over jaundice). Intoxication is not expressed. The liver is not
enlarged significantly.
Athypical forms. In 20 % of cases of VAH.
Anicteric hepatitis (prevalence among children under 6 years of age is
90 %, among children from 6‒14 years old is 40‒50 %). Anicteric hepatitis
common in infants featured by GIT manifestation likes gastroenteritis. There is
no yellowing of the color of the skin and mucous membranes, but there are
symptoms of mild form of viral hepatitis A, acute enlargement of the liver, its
pain. Increase in the level of ALT, AST, thymolysis, level of bilirubin in norm.
Worn form. Intoxication is absent or insignificant, yellowness is poorly
expressed, the level of bilirubin in serum is increased in 1,5‒2 times.
9
 Subclinical form. Completely absent clinical manifestations (more often
with VAH). Establishment of contact with a patient with viral hepatitis.
Increase in activity ALT, AST, thymol test. The most reliable is the detection of
antibodies of the Ig M class to the virus of hepatitis A.
Inaparantic form is diagnosed only on the basis of increasing the titre of
specific antibodies in the dynamics.

VIRAL HEPATITIS E
Etiology
Hepatitis E is an illness of the liver caused by hepatitis E virus, a virus
which can infect both animals and humans.
Hepatitis E was identified as an epidemic of non-A, non-B hepatitis from
Kashmir, India in 1978. Hepatitis E virus is the sole member of family
Caliciviridae, a small virus, with a positive-sense, single-stranded ribonucleic
acid (RNA) genome. The virus has at least 4 different types: genotypes
1, 2, 3 and 4. Genotypes 1 and 2 have been found only in humans. Genotype 3
and 4 viruses circulate in several animals (including pigs, wild boars, and deer)
without causing any disease, and occasionally infect humans. Hepatitis E virus
is quite thermophilic, is not resistant to thermal and chemical influences. Has
HEV Ag. It is similar to the rubella virus.
Epidemiology
Hepatitis E is an imperative health issue in developing nations,
transmitted through sullied water and happens most every now in young adults.
The hepatitis E virus is transmitted mainly through the fecal-oral route due to
fecal contamination of drinking water. The risk factors for hepatitis E are
related to poor sanitation, allowing virus excreted in the feces of infected
people to reach drinking water supplies. Other route of transmission have been
identified: ingestion of undercooked meat or meat products derived from
infected animals.
Clinical manifestations
The incubation period is from 10 to 50 days. The infected persons are
believed to excrete the virus beginning a few days before to around 3‒4 weeks
after the onset of disease. The clinical illness associated with VEH infection is
similar to VAH but is often more severe. As with VAH, the disease is acute,
chronic illness does not occur. When infection does occur in children, they
often have either no symptoms or only a mild illness without jaundice that
goes undiagnosed.
Typical signs and symptoms of hepatitis include: the appearance of
astheno-dyspeptic symptoms: weakness, worsening of appetite, possibly
nausea, repeated vomiting, abdominal pain lasting for a few days. Some persons

10
may also have abdominal pain, itching (without skin lesions), skin rash,
or joint pain.
Jaundice (yellow discolouration of the skin and sclera of the eyes), dark urine
and pale stools are present. Liver is a slightly enlarged, tender (hepatomegaly).
These symptoms are often indistinguishable from those experienced
during other liver illnesses and typically last between 2–6 weeks. Hepatitis E is
usually a mild disease which is self-limiting and resolving within 2–6 weeks.
After 1–2 months from the onset of the disease, the majority of children
undergo a complete restoration of the structure and function of the liver.
In some cases, there is a prolonged course. In adults, especially often, in
pregnant women, malignant forms with a fatal outcome are described.
In children, apparently, such forms do not occur.

VIRAL HEPATITIS B
Hepatitis B is a potentially life-threatening liver infection caused by
the hepatitis B virus. It is a major global health problem. Hepatitis B attacks
the liver, can cause both acute and chronic disease and puts people at high
risk of death from cirrhosis and liver cancer. Hepatitis B is an important
occupational hazard for health workers.
Etiology
Pathogen – is a 42 nm diameter DNA virus of the family Hepadnaviridae
It was discovered by Blamberg in 1964. The genome is represented by an
incomplete (one thread shorter than the other) double-stranded DNA ring
molecule and the associated DNA polymerase.
In virions 3 antigens are isolated: 1) HBs Ag – surface antigen;
2) HBe Ag – antigen of infectivity; 3) HBc Ag – nuclear (cow) antigen.
DNA of the virus can exist in a replicative or integrative form. With
replication, the development of an acute or chronic infectious process is
associated, integration is at the heart of the virus carrier. Replication of this
virus occurs predominantly in the liver but also occurs in lymphocytes, spleen,
kidney, and pancreas.
The hepatitis B virus is extremely stable in the external environment.
In the frozen form is kept up to 20 years, in the dried plasma – up to 25 years.
The virus is inactivated after autoclaving at 120° C after 45 minutes, dry heat
sterilization at 180° C after 60 minutes. It is perniciously affected by hydrogen
peroxide, chloramine, and formalin.
Epidemiology
The source of infection is patients with any form of infection, as well
as virus carriers. The virus is transmitted parenterally. Transmission factors
are blood and its preparations containing the virus. To infect enough 0,0001 ml

11
of blood. Also infection is possible when used without proper sterilization of
syringes, during surgery, dental treatment, scarification, blood collection,
endoscopy, acupuncture, sharing razors or toothbrushes, tattooing, body
piercing ect.
Vertical transmission is usually observed either in the case of a mother's
disease in the third trimester of pregnancy, or if the mother is a carrier of HBs
Ag. The risk of transmission is greatest if the mother also is HBeAg positive to;
70–90 % of their infants become chronically infected if untreated. In most
cases, antigenemia appears later, suggesting that transmission occurred at the
time of delivery; virus contained in amniotic fluid or in maternal feces or blood
may be the source.
Transmission is possible through unprotected sex.
The hepatitis B virus is present in high concentrations in blood, serum,
serous exudates; in moderate concentrations in saliva, vaginal fluid and semen.
Pathogenesis
Causative agent fixates on the hepatocyte and penetrates into the cell.
After that multiplication and isolation on the surface of the hepatocyte occur.
Immunological reactions aimed to elimination of the pathogen. Further
destruction of the liver cells occurs under the influence of T-lymphocytes
(killers). Damage to other organs and systems is possible.
Clinical manifestation
Viral hepatitis may develop without clinical signs or symptoms,
or with nonspecific symptoms that may appear for a short time with or
without jaundice.
1. The incubation period usually lasts 2–4 months.
2. The prodromal period often starts gradually up to 2–3 weeks. Carolis
triad: includes headache, arthralgia, rashes. The spotty papular rash appearances
on the skin of the chest, abdomen. Dyspeptic syndrome can be isolated (nausea,
vomiting), abdominal syndrome is characterized by pain in the right upper
quadrant, epigastrium. Janoti-Crosti syndrome or arthralgic syndrome is
characterized by appearance of dark urine and lightening of stool color during
prodromal period also. At the end of the period, there is an increase in liver
size, sometimes the spleen, increase of ALT, AST. This duration of this stage of
the disease may range from 2–3 days to 2–3 weeks.
3. Jaundice period is characterized by symptoms of intoxication are
intensified. Patients have fever, nausea, vomiting, abdominal pain, weakness,
decreased appetite, a feeling of heaviness. A pain in the right upper quadrant is
noted. Jaundice increases gradually over 5 to 7 days, sometimes up to 2 weeks,
it can vary from slightly yellow (lemon) to greenish-yellow. The degree
of jaundice is associated with the severity of the disease and the development
of cholestasis syndrome. In parallel, the increase in jaundice in VBH increases
in size the liver, the edge of it becomes denser and soreness is noted. The spleen
is enlarged in severe cases and with a prolonged course of the disease.
12
 4. The period of reconvalescence with the disappearance of jaundice.
Children become active, they restore their appetite, but there is still
hepatomegaly, a minor hyperfermentopathy. Disappearance of clinical
symptoms and normalization of functional liver samples occurs in 3 to 4 weeks,
and there are also cases when normalization of the clinic and biochemical
changes occurs only 4 to 6 months after the onset of the disease.
Malignant form (fulminant) of VBH
Malignant form (fulminant) of VBH is characterized by reduction of the
prodromal period. A sharp deterioration in the state of the child when jaundice
appears expressive intoxication syndrome, hemorrhagic syndrome (vomiting by
"coffee grounds"), tachycardia, emotional disorders: drowsiness during the day,
insomnia at night. Violations orientation, spoor appears at the precoma stage,
stupor appears at the coma. Liver size is reduced.
Laboratory tests: anemia, neutrophilic leukocytosis, thrombocytopenia,
acceleration of ESR, hyperbilirubinemia, biliary ubin-enzyme dissociation,
decreased prothrombin, fibrinogen.
Serologic investigation
HBsAg is the 1st serologic marker of infection to appear and is found
in almost all infected persons; its rise closely coincides with the onset of
symptoms. Because HBsAg levels fall before symptoms wane, IgM antibody
to HBcAg (anti-HBc IgM) helps to identify acute infection, as it rises early after
infection and remains positive for many months before being replaced by anti-
HBc IgG, which persists for years.
Anti-HBc is the most valuable single serologic marker of acute
VBH infection because it is present almost as early as HBsAg and continues to
be present later in the course of the disease when HBsAg has disappeared.
Anti-HBs marks serologic recovery and protection. Only anti-HBs is
present in persons immunized with hepatitis B vaccine, whereas both anti-HBs
and anti-HBc are detected in persons with resolved infection.
HBeAg is present in active acute or chronic infections and is a marker of
infectivity. The development of anti-HBe marks improvement and is a goal of
therapy in chronically infected patients.
Hepatitis В viral DNA can be detected in the serum of acutely infected
patients and chronic carriers. High DNA titers are seen in patients with HBeAg,
and typically fall once anti-HBe develops.

VIRAL HEPATITIS C
Long-term infection with the hepatitis C virus is known as chronic
hepatitis C. Chronic hepatitis C is usually a "silent" infection for many years,
until the virus damages the liver enough to cause the signs and symptoms
of liver disease.
13
 Etiology
The causative agent is the RNA genomic virus of the Flaviviridae family.
Virions of a spherical form, surrounded by a super capsid. The genome contains
a single-stranded RNA. There are 6 serotypes and more than 100 subtypes of
the virus. The virus is highly variable and induces a weak immune response.
A distinctive feature of the hepatitis C virus is the ability to persistence in the
body, which causes a high level of chronic infection ‒ 80 %. The virus is
resistant to heating up to 50° C, it is inactivated by UVI. Stability of the
pathogen in the external environment is more pronounced than in HIV.
Epidemiology
Prevalence among adults is 2 %, among children ‒ is 0.2 %, among
adolescents is 0.4 %. The reservoir and source of infection are patients with
chronic and acute forms of the disease, both with clinical manifestations and
asymptomatic. The serum and blood plasma of an infected person is contagious
during a period beginning one or several weeks before the onset of clinical
signs of the disease, and may contain the virus indefinitely.
The mechanism of transmission is similar to viral hepatitis B
(blood transfusion, sharing unsterilised needles, sharing razors or toothbrushes,
tattooing, body piercing, through unprotected sex (rare), from a pregnant
woman to her unborn baby (rare) (mother HCV+: 5 % risk, mother co-infected
with HIV: 15 % risk, all infants born to HCV-infected mothers should be tested
for anti-HCV Ab after 12 m of age)). But it is transmitted primarily through
infected blood and to a lesser extent through other biological fluids.
The high-risk groups includes people, who have been repeatedly
transfused with blood and its drugs, as well as those who have a history of
massive medical interventions, organ transplants and multiple parenteral
manipulations; drug users (the prevalence of viral hepatitis C among them
is 70‒90 %).
Pathogenesis
Hepatitis C virus appears to cause injury primarily by cytopathic
mechanisms, but immune-mediated injury may also occur. The primary immune
response to hepatitis C virus is mounted by cytotoxic T lymphocytes.
Unfortunately, this process fails to eradicate infection in most people; in fact,
it may contribute to liver inflammation and, ultimately, tissue necrosis.
Clinical manifestation
Acute infection is mostly clinically not diagnosed, occurs mainly in
subclinical, jaundiced form, accounting for up to 95 % of all cases of acute viral
hepatitis C. In the clinically manifested form of acute viral hepatitis C,
the classic signs of the disease are slightly or absent. Patients noted weakness,
lethargy, fatigue, worsening appetite, reduced tolerance to nutritional loads.
1. Incubation period lasts 2‒13 weeks, but depending on the transmission path
it can be extended up to 26 weeks.
14
2. Pre-icteric period is characterized by pain in the right hypochondrium, fever,
arthralgia, dyspeptic manifestations.
3. Icteric period is characterized by jaundice, wich occurs in 25 % of patients.
The course is usually light, the ictericity disappears quickly. The disease
is prone to exacerbation, which again causes icteric syndrome.

VIRAL HEPATITIS D
Etiology
It is caused by a small defective RNA-containing virus. The virus size is
27 nm. Its pathogenic effect is manifested in persons infected with hepatitis
B virus. For reproduction, it needs a virus-helper, which role is played by
hepatitis B virus. The hepatitis D virus envelope forms HBsAg, so there is
always a mixed infection of VDH + VBH.
The hepatitis D virus binding with the hepatitis B virus determines the
possibility of developing of superinfection (hepatitis D virus stratification on
hepatitis B virus) and co-infection (with simultaneous infection with
both viruses).
The virus is resistant to heating, the action of acids, nuclease,
glycosidases. Denaturation of the protein is achieved by treatment with alkalis
and proteases. Repeated freezing and thawing does not affect its activity.
Epidemiology
The reservoir and source of the pathogen are a sick person or a carrier.
In the spread of the virus, persons with chronic forms of viral hepatitis B who
are simultaneously infected with hepatitis D virus are of primary importance.
The patient is most dangerous in the acute period of the disease.
The mechanism of transmission is parenteral, with the same features as
in viral hepatitis B. Transplacental transmission of the hepatitis D virus from
the pregnant to the fetus. The natural susceptibility is high. Viral hepatitis D is
susceptible to all persons who are infected with or are carriers of hepatitis
B virus. The most likely development of viral hepatitis D is in chronic carriers
of HBsAg.
Pathogenesis
Infection with viral hepatitis D occurs only parenterally and only in the
presence of a reproducing virus of hepatitis B. The causative agent is built into
the genome of the hepatitis B virus, affecting its synthesis and enhancing the
replication of the latter. The disease can manifest itself as co-infection with
simultaneous infection with viruses of hepatitis B and hepatitis D and
superinfection in those cases when the virus of hepatitis D enters the body of a
person previously infected with the virus of hepatitis B (acute or chronic course
of viral hepatitis B). Replication of the hepatitis D virus occurs in the liver cells.

15
The pathogenesis of hepatocyte damage in this disease has not been fully
deciphered, but it is believed that the virus has a direct cytopathic effect on
liver cells.
Clinical picture
Symptoms (simultaneous infection by viruses of hepatitis B and D) are
generally identical to those in VBH. Features include a shorter incubation
period, the presence of a prolonged high fever, the frequent occurrence of skin
rashes and migratory pain in large joints. The course is relatively favorable, the
chronization risk is not exceeded, as in VBH.
In cases of coinfection, the clinical course of the disease is similar to the
clinical manifestations of viral hepatitis B, but with a predominance of severe
course. Fulminant forms with co-infection arise from 5 to 30 % of cases. In
superinfection, a sharp increase in the course of viral hepatitis B with a
pronounced insufficiency of liver function and the development of a large
number of chronic forms leading to the rapid formation of liver cirrhosis
are observed.

DIFFERENTIAL DIAGNOSIS OF VIRUS HEPATITIS

Character Hepatitis A Hepatitis Hepatitis Hepatitis Hepatitis E
istic Virus B Virus C Virus D Virus Virus
Nucleic RNA DNA RNA RNA RNA
acid
Sourse of Person with Person Person Person Person with
infection icteric, with with with icteric,
anicteric, icteric, icteric, icteric, anicteric,
subclinical anicteric, anicteric, anicteric, subclinical
forms Subclinical subclinical subclinica forms
forms, forms l forms
Mechanis Fecal-oral Parenteral, Parenteral, Superinfe Fecal-oral
m of sexual, sexual, ction,
transmissi Perinatal Perinatal coinfectio
on n
Major Fecal-oral Blood Blood Needle Water
transmissi
on
Duration Acute Acute, Acute, chronic acute
chronic chronic
Incubation 15–45 40–180 20–120 30–180 14–60
period
(days)

16
Character Hepatitis A Hepatitis Hepatitis Hepatitis Hepatitis E
istic Virus B Virus C Virus D Virus Virus
Variants Dyspepsia Arthralgia, Dyspepsia As VBH Dyspepsia
of syndrome,“Fl asteno- syndrome, syndrome,“Fl
prodromal u like vegetative asthenove u like
period syndrome“, syndrome, getatic syndrome“
asthenovegeta mixed syndrom
tic syndrom variant
Icteric disappearance intoxicatio predomina As VBH after
period of n after the ntly in an appearance
intoxication appearance icteric or of jaundice
symptoms of jaundice subclinical intoxication
after are usually form does not
appearance of amplified diminish
jaundice
Severity predominantl moderately predomina More severe course
y mild and and severe ntly mild severe in pregnant
moderately course of and that VBH women,
severe course the disease moderatel possible the
of the disease y severe development
course of of cholestatic
the disease forms

Serologic IgM anti-HA HBsAg Anti-HCV Anti- Anti-HEV

diagnosis HDV
Epidemics Yes No No No Yes
Chronicity No Yes Yes Yes No
Liver No Yes Yes Yes No
cancer

DIAGNOSIS OF VIRAL HEPATITIS

1) Complaints (see clinic)

2) Medical history (hepatomegaly , splenomegaly, meteorism, bradycardia,
visual assessment of urine (dark))
3) Laboratory investigations:
CBC: leukopenia , lymphocytosis , thrombocytopenia, with fulminant form
of acute VBH – leukocytosis.
Urinal test: the appearance of bile pigments (mainly direct bilirubin), urobilin.
17
Biochemical blood test: bilirubinemia (direct fraction), hypertransaminase
(ALT and AST increased in times), dysproteinemia, an increase in the markers
of cholestasis, increase in thymol test, decrease in the sulem test).
Cytolysis syndrome: increase of ALT, AST.
Cholestasis syndrome: an elevation of total bilirubin, cholesterol, APF,
γ-glutamyltranspeptidase (is usually observed with jaundice).
Mesenchymal inflammatory syndrome: an elevation of immunoglobulins,
an increase in thymol sample, a decrease in the sulemic test.
A syndrome of hepatic-cellular insufficiency: a decrease in the prothrombin
index, serum albumin concentration, cholesterol, total bilirubin.
4) Serological and virological tests:
Viral hepatits A: in serum by ELISA: anti-HAV IgM (activity indicator
infection), anti-HAV IgG (the indicator of the transferred infection),
RNA-HAV by PCR in blood.
Virus hepatits E: in serum by ELISA: anti-HEV IgM (activity indicator
infection), anti-HEV IgG; by PCR in blood: HEV RNA.
Virus hepatitis B in serum by ELISA:
- anti-HBcor IgM (Ab to nuclear Ag) ‒ the earliest sensitive serum markers of
VBH. Indicates the replication of the virus and the activity of the process in the
liver; its disappearance serves as an indicator of either sanation of the organism
from the pathogen, or development of the integrative phase of HBV infection;
- anti-HBcor IgG persists for many years; evidence of an existing or previously
transmitted infection;
- anti-HBe (Ab to e-Ag) in combination with anti-HBc IgG and anti-HBs
indicates the complete completion of the infectious process;
- HBsAg is detected 1‒10 weeks after infection, its appearance precedes the
development of clinical symptoms and increased ALT/AST activity. With an
adequate immune response, it disappears 4‒6 months after infection;
- HBeAg indicates viral replication in hepatocytes;
- HBsAg is detected in serum;
- virus of hepatitis B ‒ HBV DNA and DNA polymerase are diagnostic markers
of viral replication.
VCH
-anti-HCV Ig is detected in the blood no earlier than 8 weeks after infection.
It is present in the blood in approximately half of patients with clinically
manifested асute VCH in the onset of the disease. With subclinical infection,
Ab usually appears much later,
- HCV RNA - the earliest biochemical marker of infection, occurs within
a period of several days to 8 weeks after infection.
In cases of recovery from acute VCH, the viral RNA disappears from the blood
within 12 weeks after the onset of the first symptoms.

18
Viral hepatitis D: in serum by ELISA: anti-HDV IgM; by PCR in blood: HDV
RNA (replication marker of VDH).
5) Additional methods of research
Stool analysis: decrease in the content or absence of stercobilin due to the
cessation of bile in the intestine; the appearance of stercobilin in the feces
during the icteric period of acute viral hepatitis is evidence of the resolution of
jaundice.
Screening of hepatocellular carcinoma: concentration in the blood of
α-fetoprotein . This research should be carried out in dynamics.
Instrumental studies: ultrasound of the liver and spleen (increased echogenicity
of the parenchyma, compaction along the vessels of the liver).
A liver biopsy is necessary to assess the degree of liver damage.
CT of abdominal organs; endoscopic investigation.

TREATMENT OF VIRAL HEPATITIS

Acute viral hepatitis: treatment is predominantly symptomatic -
detoxification infusion therapy, enterosorbents, ursodeoxycholic acid with
expressed cholestasis, in severe cases ‒ prednizolone.
Treatment of mild form acute hepatitis
Basic treatment includes bed regimen up to intoxication disappear, half-bed
regimen (up to icterus disappear, normalization of ALT, AST), special diet (diet
N 5), excluding heavy fats (like pork), spices, fried foods, "fast food"; the diet
must be rich by metionine, lecithin, and choline to stimulate synthesis of
proteins and enzymes in the liver. Diet with normal value of proteins and
vitamins, with restriction of fats and carbohydrates is administered, also restrict
salt, a lot of drinks. Foods boiled, steamed and baked are recommended; food
taking 5 times daily.
Treatment of moderate form acute hepatitis:
basic therapy, per oral detoxication 40‒50 ml/kg with water balance
control; enterosorption 1‒2 wks (in case of cholestatic variant); choleretics
from the
3-d week of disease (cholagon, allocholum, cholenzym, galstena, hepabene).
Treatment of severу acute hepatitis
basic therapy; intravenous detoxication therapy (total – 50‒100 ml/kg/day):
0,9 % NaCl, Ringer’s solution, Ringer’s lactate solution, 5 % glucose, albumin
5 ml/kg;
enterosorption 2‒3 wks, lactulose for 10‒14 days, desoxycholic acid
(ursophalk) in case of cholestasis 10 mg/kg, prednizolone (in possibility of
fulminant form development) and for infants before 1 year with unfavorable

19
premorbid background): in daily dose 2‒3 mg/kg 4 times per day divided in
equal doses during 7‒10 days.
- Hepatoprotectors in severe cases in posticteric period; Heptral (tabl. – 0.4 g,
amp. – 0.4 g) 1‒2 tabl. 3 times a day (20‒25 mg/kg/day), Essentiale (caps.,
amp.) 1‒2 cap. 3 times a day, Carsil (dragee) 1‒2 dragee 3 times a day,
Hepabene 1‒2 dragee 3 times a day, Thiotriazolinum 1 tabl. 3 times a day,
Chophytol 1‒2 tabl. 3 times a day.
Specific antiviral therapy is indicated in
-acute viral hepatitis C. Usually, interferon alfa is used at 3 million IU per
subcutaneously for a week in combination with ribavirin, which significantly
reduces the risk of CHC development.
Etiologic treatment chronic viral hepatitis B:
Interferon alfa at a dose of 5 million IU / day subcutaneously or 10 million IU 3
times a week for 4‒6 months. Peginterferon alfa-2 a (PEGASYS) dose of
180 mcg, subcutaneously once a week. The duration of treatment is 1 year.
Lamivudine is prescribed for 100 mg/day orally. The duration of the course of
treatment is 1 year.
Etiologic treatment chronic viral hepatitis C:
Combination therapy is usually performed: peginterferon alfa-2 and 180 mg/kg
subcutaneously once a week with ribavirin or peginterferon alfa-2b at
1,5 mg/kg subcutaneously once a week with ribavirin, the dosage of which
depends on body weight.
Monotherapy with peginterferon alfa-2a or alpha-2b is performed in the
presence of contraindications to taking ribavirin.
Etiologic treatment chronic viral hepatitis D:
treatment of chronic hepatitis D is still an unsolved problem. It is recommended
to use interferon alfa in high doses (9‒10 million IU subcutaneously every other
day for at least 48 weeks), but the effectiveness of such therapy is rather low.
Treatment of acute hepatic insufficiency
1. Mode ‒ strict bedding
2. Diets 5, 5a with protein restriction up to 40 % per day
3. Catheterization of vessels and appointment: Prednisolone 15 mg/kg/day
every 4 hours without a night break
4. Dezintoxication therapy (5 % glucose solution, 0,9 % NaCl solution, albumin
(10 ml/kg/day in/v drip)) under the control of diuresis
5. Extracorporeal methods of detoxification with ineffective therapy
(plasmaphoresis)
6. Hyperbaric oxygenation
7. In case of edematous-ascitic syndrome ‒ correction of electrolyte balance and
protein composition of blood
8. K+ retaining diuretics (veroshpiron, triampur, spirinolactone)

20
9. Freshly frozen plasma 10 ml/kg (source of factors of blood coagulation)
10.Heparin 100-150 IU/kg/day for threat DIC-syndrome (the first portion
(1/4 of the daily) in/v the drip with fresh-frozen plasma, the subsequent
subcutaneous)
11. Proteolysis inhibitors (trasilol, countercracker, gordoks) at age doses with
the development of DIC syndrome
12. Antibacterial therapy (prevention of infectious complications)
13. Gastric lavage and high cleansing enema
14. Lactulose preparations

PREVENTION OF VIRAL HEPATITIS

Nonspecific prevention includes:
- for viral hepatitis A and E: careful handwashing is necessary, particularly after
changing diapers and before preparing or serving food, drinking pure water.
- for viral hepatitis B, C, D: activities to prevent drug addiction and
promiscuous sexual intercourse; mandatory check for markers of viral hepatitis
blood products and organs for transplantation, care should be taken when
medical workers are extremely, treatment of infectious materials (blood and
other medical fluids) or medical devices that come in contact with them.
Patients infected with virus of hepatitis A are contagious for 2 wk before
and about 7 days after the onset of jaundice and should be excluded from
school, child care, or work during this period. In hospital settings, contact and
standard precautions are recommended for 1 wk after onset of symptoms.
Specific prevention is designed only for hepatitis B in our country.
Vaccination is considered the most effective protection against hepatitis
B infection to date. Vaccination against hepatitis B was included in the calendar
of mandatory vaccinations. Three vaccinations against hepatitis B are carried
out in the first year of the child's life, and the first time the vaccine is done in
the maternity ward, several hours after the birth of the baby, then on the 1st
month and at the 6th month of life. Adolescents and adults are vaccinated
against hepatitis B on a voluntary basis, and representatives of the risk group
are urged to urgently recommend such an inoculation. Recall that the risk group
includes employees of medical institutions; patients who received blood
transfusions; drug addicts ect.
The availability of two inactivated, highly immunogenic, and safe VAH
vaccines has had a major impact on the prevention of VAH. In some countries
vaccination against hepatitis A is used as a specific prophylaxis for hepatitis A,
but it is not mandatory in many countries and is not included in the calendar of
mandatory vaccinations. Any person who has no contraindications to
administering the vaccine can be immunized. Vaccination against hepatitis

21
A forms an immune system that protects a person from the disease for
6‒10 years. Pre-exposure prophylaxis and post-exposure prophylaxis VAH
(travelers to endemic regions) uses VAH-specific immunoglobulin (Ig).

QUESTIONS FOR SELF-CONTROL

1. Viral hepatitis A and E. Etiology, epidemiologic features, pathogenesis.
Classification. Clinic of various forms. Laboratory diagnosis. Principles of
treatment and prevention.
2. Viral hepatitis B. Etiology, pathogenesis. Features of course in children of
early age. Laboratory data. Treatment. Features of diagnostics and course
of viral hepatitis C, D, E in children.
3. Viral hepatitis C. Etiology, epidemiologic features, pathogenesis.
Classification. Clinic. Laboratory diagnosis. Principles of treatment
and prevention.
4. Viral hepatitis D. Etiology, epidemiologic features, pathogenesis.
Classification. Clinic. Laboratory diagnosis. Principles of treatment
and prevention.

CASE STUDIES
Case №1
An 11-year-old child has been diagnosed hepatitis C. Which of the
following may be considered in the treatment of chronic hepatitis C infection?
The standart answer: Combination therapy is usually performed:
peginterferon alfa-2 and 180 mg/kg subcutaneously once a week with ribavirin
or peginterferon alfa-2b at 1,5 mg/kg subcutaneously once a week with
ribavirin, the dosage of which depends on body weight.
Case №2
The child, 8 years old, complains of pain in knee joints, weakness, jaundice
of the skin and visible mucous membranes, appearing of the rash on limbs,
around joints. The spleen is enlarged to 2 cm and liver ‒ to 3 cm, moderately
compacted. 4 months ago the child had operation. In biochemical blood tests:
total bilirubin is 98,26 mcmol/l: direct ‒ 66, AST ‒ 2.12, ALT ‒ 2.65. Hepatitis
B was suspected. What disease must be differentiated at the first place?
The standart answer: We must think about other variants of viral hepatitis
(A, C, E, D). The operation that child had 4 months ago, testifies in favor of
hepatitis with a parenteral route of transmission (VBH, VCH, VDH). Serological
methods for the detection of specific antibodies to hepatitis viruses will help
determine the exact diagnosis.

22
 Case №3
The boy,14 years old, was treated because of the hepatis B, moderate
degree. He was discharged from hospital in satisfactory condition.
In biochemical blood test: total bilirubin is 15.39 mcmol/l, AST ‒ 0,72,
ALT ‒ 0.78. In what time is it necessery to repeate biochemical test?
The standart answer: In 1, 3, 6, 9, 12 months.  If in 12 months after
discharge from the hospital, the child has all clinical and laboratory parameters
in the norm, one can speak about his recovery.
Case №4
A family has recently moved to your area from China. The mother tells
you that her hepatitis B screen was positive on arrival to the United States. She
has a 2-month-old child and asks you what signs of infection would be in the
child. What is the most common presentation of congenital hepatitis B?
The standart answer: The most common presentation of congenital
hepatitis B are icteric sclera, mucous membranes and skin. If the child has such
signs, the mother with the child should urgently go to the hospital.
Case №5
A 6-year-old boy has been diagnosed as having mild form of viral
hepatitis. What is the most important in treatment?
The standart answer: The most important in treatment of mild form of
viral hepatitis is basic therapy: regimen (bed regimen up to intoxication
disappear, half-bed regimen up to icterus disappear, normalization of ALT,
AST) and diet (diet N 5), a lot of drinks.

23
 TESTS

1. Incubation period at viral hepatitis A:

a) 3‒7 days
b) 8‒10 days
c) 7‒14 days
d) 7‒21 days
e) 10‒45 days
Answer e)

2. What is duration of dispensary observation hepatitis B:

a) 3 months
b) 6 months
c) 9 months
d) 12 months
e) 10 months
Answer d)

3. The jaundice period of viral hepatitis A is characterized by the increase of:

a) Indirect bilirubin, tymol test
b) Cholesterol, ALT
c) Tymol test, alkaline phosphotase
d) Cholesterol, beta-lipoproteins, indirect bilirubin
e) ALT, AST, direct bilirubin
Answer e)

4. A 10 year old boy suffers from chronic viral hepatitis type B with
maximal activity. What laboratory test can give the most precise characteristic
of cytolysis degree?
a) Transaminase test
b) Weltman's coagulation test
c) Takata-Ara test
d) Prothrombin test
e) Test for whole protein
Answer a)

5. Name of Hepatitis A markers

a) Anti-HAV IgM and anti-HAV IgG
b) Anti-HCV IgM, viral RNA
c) Anti-HEV IgM, viral RNA
d) Anti-HBV IgM and anti-HBV IgG
e) HBsAg, HbeAg, HbcAg, anti-HBV IgM, IgG
Answer a)
24
6. Incubation period for hepatitis B is:
a) 45 days
b) 180 days
c) 360 days
d) 90 days
Answer b)

7. Level of bilirubin at the viral hepatitis A mild form is:

a) 10‒15 mcmol/L
b) not higher than 82 mcmol/L
c) 100‒200 mcmol/L
d) 150‒200 mcmol/L
e) more than 200 mcmol/L
Answer b)

8. Total bilirubin ‒ 70 mmol/L, direct ‒ 26 mmol/L, indirect ‒ 44 mumol/

L АSТ ‒ 6,2 mmol/L, АLТ ‒ 4,8 mmol/L. What mechanism underlies the
transaminase level increase of this patient?
a) Cytolysis of hepatocytes
b) Failure of the synthetical function of the liver
c) Hypersplenism
d) Intrahepatic cholestasis
e) Failure of bilirubin conjugation
Answer a)

9. The term of hepatitis B active prophylaxis according vaccination schedule

a) First 12 hours of life, 1, 3, 5 months
b) Infant vaccinated at birth; at 1‒2 m; at 6‒18 m
c) First12 hours of life, 1, 6, 12 months
d) 3‒5 days, 7, 14 years
e) 3, 4, 5 months, revaccination in 18 month
Answer b)

10. What is etiology of hepatitis C?

a) Picornaviruses family
b) Adenoviruses
c) Ortomyxoviruses
d) Hepadna viruses family
e) Flaviviruses family
Answer e)

25
 REFERENCE

1. Fedortsiv O. Ye. Manual of children's infectious diseases /

O.Ye. Fedortsiv, I. L. Horishna, I. M. Horishniy. ‒ Ternopil:
Ukrmedknyha, 2010. ‒ 382 p.
2. Manual of Childhood Infections: the blue book (Oxford specialist
handbooks in pediatrics) /Mike Sharland, Andrew Cant and al. ‒
New York: Oxford University Press Inc., 2011. ‒ 881 p.
3. Nelson textbook of Pediatrics 20th ed. /Kliegman RM, Behrman RE,
Jenson HB, Stanton BF. Philadelphia: Saunders Elsevier, 2016. ‒ 5315 p.
4. Oxford Textbook of Medicine: Infection / David Warrell, Timothy M.
Cox, John Firth, Mili Estee Torok. ‒ Wiley-Blackwell, 2012.

26
ДЛЯ НОТАТОК

27
 Навчальне видання

Ржевська Ольга Олександрівна

Зімницька Тетяна Василівна

ДИФЕРЕНЦІЙНА ДІАГНОСТИКА ТА ЛІКУВАННЯ

ВІРУСНИХ ГЕПАТИТІВ У ДІТЕЙ
Методичні рекомендації для самостійної роботи іноземних студентів
5 та 6 курсів медичного факультету
з дисципліни «Педіатрія та дитячі інфекційні хвороби»

DIFFERENTIAL DIAGNOSIS AND TREATMENT

OF VIRAL HEPATITIS IN CHILDREN
Methodological recommendations for student’s self‐work in subject
“pediatrics and pediatric infections” for international
students of 5th and 6th courses of medical faculty

Комп’ютерне верстання Н.Є. Пруднік.

Макет обкладинки І.М. Дончик

Формат 60х84/16. Ум. друк. арк. 2,08. Тираж 100 пр. Зам. № ..........

Видавець і виготовлювач
Харківський національний університет імені В. Н. Каразіна,
61022, м. Харків, майдан Свободи, 4.
Свідоцтво суб’єкта видавничої справи ДК № 3367 від 13.01.09

Видавництво ХНУ імені В. Н. Каразіна

Тел. 705-24-32
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