Hepatitis C in the newborn
Criteria of Hepatitis Severity (in icteric period)
Signs
Mild
Moderate
Severe
Degree of intoxication in
preicteric period
Mild, short
Moderate
Severe
Body temperature
subfebrile
t 38-39 ℃ (in preicteric
period)
t 39 ℃ and more
Jaundice
Mild
Mild-to moderate
Severe
Liver size increases
Up to 2 сm
On 2-5 cm
More than 5 cm
Bilirubin increases
Indirect bilirubin
increases
Up to 85 μmol/l Up to
25
85-200
25-50
> 200
> 50
Aminotranspherases
level
5-10 times more than
normal
10-15 times more
than normal
15-30 times more
than normal
Prothrombin index
70-80 %
60-70 %
< 60%
Tymol test
Mildely increased
Moderately increased Severely increased
Normalization of the
liver sizes
On 25-35
th
day from
the
beginning
On 40-50
th
day
On 50-60
th
day
When the jaundice
appears the toxic sign
Decreases
Continues for 2-3
days
Continues,
sometimes
increases
Splenomegaly
––
In 1.5 %
Is typical
Diuresis
Normal
Decreased
Markedly
decreased
Sulemic test
Normal
Normal
Decreased
Icteric
phase course
7-10 days
1-2 wks
2-3 wks
Posticteric period
•
Urine becomes lighter
•
Stools becomes darker
•
Jaundice decrease
•
Decreasement of the liver sizes
•
Normalization of bilirubin, ALT and AST, other indexes.
•
Anti-HAV Ig G, (Hepatitis A). The presence of anti-HAV IgG in the absence of IgM
indicates past infection or vaccination.
• Anti-НВс IgM, anti-Нве IgM, later- anti-НВс (total) IgM and anti-НВс IgG (Hepatitis
B).
•
Anti-НВс IgM, anti-Нве IgM, later- anti-НВс (total) IgM and anti-НВс IgG and anti-
HDV IgG (Hepatitis D).
•
Anti-HCVcore IgG (past Hepatitis C).
•
Anti-HCVcore IgG, anti-HCV NS in Hepatitis C latent phase.
•
Anti-HCVcore IgM and IgG (with IgM predominance), anti-HCV NS and HCV- RNA in
Hepatitis C reactivation phase.
•
Anti-HEV Ig G (Hepatitis E).
•
anti-E2 is usually detected only after the loss of HGV RNA in the serum. Anti-E2 can
persist for years after clearance of the virus and is therefore a marker of recovery from
HGV infection (Hepatitis G).
Liver biopsy is the most accurate method of evaluating the extent of Hepatitis C virus–
related liver disease. Liver biopsy is recommended for all patients before they start antiviral
therapy.
Fulminant Hepatitis criteria:
-
Acute hepatic failure
-
Confusion and drowsiness, somnolence, disturbances in sleep pattern
-
Delirium (mental confusion) and convulsions
-
Coma I-II
-
Hepatic smell form the mouth
-
Hemorrhagic syndrome (Gastrointestinal bleeding)
-
Decreasing of diuresis
-
Liver decreases in size
-
Total bilirubin increases
-
Coagulopathy (Prothrombin time is prolonged)
-
Decreased ALT, AST
-
Decreased protein (albumen)
Atypical (unicteric, effaced, subclinical) forms criteria:
-
Contact with patient who had hepatitis
-
Hepatomegaly
-
Increasing of ALT, AST, GGTP
The clinical picture of GBV-C infection is commonly similar to that of the subclinical and
anicteric types of hepatitis with normal or low aminotransferase activities. GBV-C-associated
hepatitis runs with normal biochemical parameters in 75% of patients. There are reports on the
occurrence of acute, fulminant and chronic (mild and moderate) Hepatitis And hepatic fibrosis.
Coinfection of HGV with Hepatitis B, C, and D viruses is significantly more frequently
detected than monoinfection. Hepatitis G infections may persist indefinitely in
immunocompromised persons, but frequently resolves in immunocompetent persons.
Outcome of the disease
For HAV, HEV
-
Recovering
-
Residual fibrosis of liver (posthepatitis hepatomegaly)
-
Biliary dyskinesia
-
Chronic cholecystitis and cholecystocholangitis
-
Chronic HEV infection in immunocompromised persons
For HBV, HCV, HDV
-
Recovery
-
presence of RNA (GBV-C) without biochemical or histological signs of liver disease
-
Fulminant hepatitis (rare)
-
Residual fibrosis of liver (posthepatitis hepatomegaly)
-
Biliary dyskinesia
-
Chronic cholecystitis and cholecystocholangitis
-
Development of chronic hepatitis (Patients with chronic Hepatitis B infection can be
immune tolerant or have an inactive chronic infection without any evidence of active
disease, and they are also asymptomatic. Patients with chronic active hepatitis, especially
during the replicative state, may have symptoms similar to those of acute hepatitis);
-
Cirrhosis which may result in portal hypertension and liver failure
-
Hepatocellular carcinoma
-
Autoimmune manifestations, often including antinuclear antibodies and smooth muscle
antibodies
-
Death
Signs of chronic hepatitis:
-
Hepatomegaly
-
Splenomegaly
-
Muscle wasting
-
Palmar erythema
-
Spider angiomas
-
Vasculitis (rarely)
Signs of liver cirrhosis:
-
Ascites
-
Jaundice
-
History of variceal bleeding
-
Peripheral edema
-
Gynecomastia
-
Testicular atrophy
-
Abdominal collateral veins (caput medusa)
Diagnosis example: Hepatitis A, typical form, icteric period, mild severity, acute course.
Differential diagnosis
Prejaundice period:
-
viral upper respiratory tract infections
-
intestinal infection
-
acute appendicitis
-
diseases caused by parasites
-
acute pancreatitis
Jaundice period:
-
suprahepatic icterus (Hemolytic anemia),
-
hepatic icterus (Gilbert, Krigler-Nadjar syndrome, Infectious mononucleosis,
Leptospirosis, Pseudotuberculosis, Congenital liver diseases, Drug-induced hepatitis,
Mushroom toxicity, Autoimmune Hepatitis, Liver Abscess),
-
subhepatic icterus (Biliary obstruction, Cholangitis, Cholecystitis).
Differential diagnosis of Viral hepatitis
Signs
HB
HA
HC
HE
HD
Patients age
All age
groups
Elder than 1
yr.
All age
groups
Elder than 1
yr.
All age
groups
Incubation
period
2-6 mo.
14-45 days
2 wks. - 3
mo.
15-45 days
2 wks. - 6
mo.
Beginning
Subacute
Acute
Subacute
Acute
Acute
Intoxication in
preicteric period
Mild
Moderate
Mild
Moderate
Often
moderate
Intoxication in
icteric period
Severe
Mild
Absent or
mild
Absent or
mild
Severe
Allergic rashes
May be
present
Absent
May be
present
Absent
May be
present
Severity
Often
moderate and
severe
Mild and
moderate
Mild and
moderate
Mild
Severe and
fulminant
Duration of the
icteric period
3-5 wks
1-1.5 wks
2 wks
1-2 wks
2-8 wks
Transformation
in chronic
hepatitis
Often -
primary
chronic
–
In 50 %
Possible in
immunocomp
romised
person
Often
Tymol test
Often normal Elevated
High
High
Moderately
elevated
Specific markers HBsAg
HBeAg
anti НВс IgМ
Anti HAV
IgМ
Anti HCV Ig
RNA HCV
Anti HEV
HBsAg, anti
НВс, anti
HDV IgМ
Treatment:
Basic treatment of an acute hepatitis:
-
bed regime up to toxic signs disappear,
-
semi-bed regime (up to icterus disappear, normalization of ALT, AST),
-
special diet:
•
Exclude heavy fats (like pork), spices, fried food, and “fast food”; avoid stimulators of
gastrointestinal secretion; the diet should be rich with 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, carbohydrates and salt.
•
Boiled, steamed and baked food is recommended; meals 5 times daily.
Treatment of mild hepatitis
– only basic therapy
Treatment of moderate hepatitis
-
basic therapy
-
peroral detoxication 40-50 ml/kg with water balance control
-
enterosorption 1-2 wks (in case of cholestatic variant)
-
choleretics in the recovery period:
•
cholagon,
•
allocholum,
•
cholenzym,
•
galstena,
•
hepabene.
Treatment of severe hepatitis
•
basic therapy,
•
intravenous detoxication (totally – 50-100 ml/kg/day):
-
0.9 % NaCl, Ringer’s solution,
-
Ringer’s lactate solution,
-
5 % glucose,
-
albumen 5 ml/kg;
•
enterosorption 2-3 wks,
•
lactulose for 10-14 days in age appropriate doses,
•
deoxycholic acid (ursofalk) in case of cholestasis 10 mg/kg,
•
prednisolone (in possibility of fulminant form development) and for infants under 1 year
with unfavorable premorbidity): in daily dose 1-3 mg/kg 4 times daily divided in equal
doses , in a course of 7-10 days,
Treatment of fulminant form
•
straight bed regimen,
•
diet with protein restriction up to 40 % of an age requirements,
•
intravenously:
-
prednisolone 10-15 mg/kg/day in 4 equally divided doses,
-
detoxication therapy (totally – 50-100 ml/kg/day) with diuresis control:
-
0.9 % NaCl, Ringer’s solution,
-
Ringer’s lactate solution,
-
5 % glucose,
-
albumen 5 ml/kg;
•
extracorporeal detoxication in case of ineffective previous therapy (plasmapheresis),
•
hyperbaric oxygenation,
•
in case of edema, ascytis – water-electrolyte balance correction,
• K-serving diuretics (verospiron, triampur),
•
Fresh frozen plasma 10 ml/kg as donator of coagulation factors,
•
Heparin 100-300 IU/kg in possibility of DIC-syndrome development,
•
Protease-inhibitors (trasilol, contrical, gordox) in the age appropriate doses in case of
DIC-syndrome development,
• Antibacterial therapy for bacterial complication prophylaxis (less hepatotoxic medicine),
•
Enema and gastric lavage,
•
Lactulose for 10-14 days.
Liver transplantation is indicated in patients with fulminant liver failure. Patients with
evidence of decompensated liver disease or fulminant liver failure should be immediately
transferred to a center capable of performing a liver transplantation.
Hepatitis B antiviral treatment
From the time of initial diagnosis, optimal management of Hepatitis B virus (HBV) infection
requires a lifetime of routine monitoring, even when patients are asymptomatic. The aims of
treatment of chronic Hepatitis B are to achieve sustained suppression of HBV replication and
remission of liver disease. The ultimate goal is to prevent cirrhosis, hepatic failure, and
hepatocellular carcinoma (HCC). Children with HBV infection may not need treatment until
well into their adolescent years or adulthood.
Either interferons (IFN-a2b and peginterferon-a2a) or nucleoside or nucleotide analogues
(lamivudine, adefovir, entecavir, tenofovir), may be used as monotherapy or in combination.
Interferon alfa 2b (3 million Units/m² IM/SC 3 times/wk for 1 wk; increase to 6 million U/m² 3
times/wk SC for 16-24 wk; not to exceed 10 million Units/dose 3 times/wk ) use has a defined,
self-limited course; in contrast, therapy with nucleoside or nucleotide analogues can be long-
term, often indefinite treatment.
PEG-INF-alfa-2a is indicated for the treatment of adults with HBeAg-positive and HBeAg-
negative chronic Hepatitis B infection
Lamivudine (≥2 years: 3 mg/kg PO qDay; not to exceed 100 mg/day) is now considered
first-line therapy.
Adefiovir (≥12 years old: Administer as in adults, 10 mg PO qDay).
Entecavir is indicated for treatment of CHB with evidence of active viral replication and
either evidence of persistent elevations in serum aminotransferases (ALT or AST) or
histologically active disease in children ≥2 years and weigh at least 10 kg Administer PO once
daily
–
10-11 kg: 0.15 mg (3 mL)
–
>11-14 kg: 0.2 mg (4 mL)
–
>14-17 kg: 0.25 mg (5 mL)
–
>17-20 kg: 0.3 mg (6 mL)
–
>20-23 kg: 0.35 mg (7 mL)
–
>23-26 kg: 0.4 mg (8 mL)
–
>26-30 kg: 0.45 mg (9 mL)
–
>30 kg: 0.5 mg (10 mL oral solution or one 0.5-mg tab)
Tenofovir (8 mg/kg PO qDay; not to exceed 300 mg/day) is indicated for chronic Hepatitis B
in children aged 2 years or older.
Hepatitis C antiviral treatment
For acute Hepatitis C virus (HCV) infection, supportive care is the mainstay of treatment.
Early initiation of antiviral therapy is not defined.
Treatment of chronic HCV infection has two goals. The first is to achieve sustained
eradication of HCV (ie, SVR), which is defined as the persistent absence of HCV RNA in serum
12 weeks after completing antiviral treatment. The second goal is to prevent progression to
cirrhosis, hepatocellular carcinoma (HCC), and decompensated liver disease requiring liver
transplantation.
In chronic HCV infection, the goal is to identify complications and suitable candidates for
antiviral therapy. Priority should be given to:
-
Patients with advanced fibrosis, those with compensated cirrhosis, liver transplant
recipients, and those with severe extraheptic complications.
-
patients at high risk for liver-related complications and severe extrahepatic Hepatitis C
complications.
-
patients whose risk of HCV transmission is high and in whom HCV treatment may result in
a reduction in transmission (eg, men who have high-risk sex with men, active injection drug
users, incarcerated persons, and those on hemodialysis).
The World Health Organization recommends treatment to all individuals aged 12 years or
older diagnosed with HCV, regardless of their disease stage.
Long-term monitoring is essential because the risk of liver cancer is high.
The first direct-acting antiviral drugs were approved for adolescents in 2017. Sofosbuvir
(Sovaldi, 400 mg PO qDay with weight-based ribavirin dose in 2 divided doses with food as
-
35-47 kg: 15 mg/kg/day
-
47-49 kg: 600 mg/day
-
50-65 kg: 800 mg/day
-
66-80 kg: 1000 mg/day
-
>80 kg: 1200 mg/day).
And the combination product, ledipasvir/sofosbuvir ( Harvoni), 1 tablet (90mg/400mg) PO
qDay for 12-24 wks, depending on previous treatment and presence of cirrhosis), is approved for
chronic HCV infection in pediatric patients aged ≥12 years or who weigh at least 35 kg.
Sofosbuvir is indicated for HCV genotypes 2 or 3 and is used in combination with
ribavirin.
Ledipasvir/sofosbuvir
is
indicated
for
HCV
genotypes
1,
4,
5,
or
6.
Glecaprevir/pibrentasvir ( Maviret) was approved for adolescents in April 2019. Treatment-
naïve adolescents aged 12-17 yr, or weighing at least 45 kg (99 lb) with chronic Hepatitis C
virus (HCV) genotypes 1-6 without cirrhosis or with compensated cirrhosis 3 tablets (ie, 300
mg/120 mg total dose) PO once daily with food for 8-16 wks, depending on previous treatment
and presence of cirrhosis.
Alpha interferon (IFN) results in a sustained response in fewer than 20% of patients, and
adverse effects are often problematic. The response rate is lower for individuals infected with
genotype 1, the most common genotype that causes infection, and the less common genotype 4.
Pegylated IFN (the addition of polyethylene glycol to the drug) results in significantly
higher rates of response, especially with non–genotype 1 Hepatitis C virus (HCV) infections.
Peginterferon alfa-2b (PEG Intron) plus ribavirin (Rebetol) is approved for children aged 3 years
or older, whereas peginterferon alfa-2a (Pegasys) plus ribavirin (Copegus) is approved for children
aged 5 years or older.
Hepatitis D antiviral treatment
No pharmacologic treatment for HDV has been approved. Peginterferon alfa-2a (PEG-IFNa2a)
and nuceloside analogues have been used to manage chronic HBV infection, but only PEG-IFN has
shown anti-HDV activity. The efficacy rate of interferon-based therapy does not exceed 30%, with
frequent termination of therapy owing to serious side effects, and the relapse rate is very high.
Hepatitis E antiviral treatment
Ribavirin monotherapy (600–1000 mg/day) for at least 3 months seems to be the first treatment
option for transplant recipients with chronic Hepatitis E. Also sofosbuvir, a nucleotide analogue,
inhibits RNA replication of HEV genotype 3 in vitro.
Hepatitis G antiviral treatment
In patients co-infected with HCV and HGV, interferon has similar efficacy with regard to both,
but the responses of the two viruses are independent.
Discharge from the hospital, supervision, and control in case of Acute Hepatitis:
*
patients with mild and moderate forms can be treated at home;
• discharge on 15-20
th
day of illness is possible with the remained hepatomegaly, slightely
increased ALT, AST, dysproteinemia);
• Supervision of the patient should be continued in an outpatient department: first examination –
in 7 days after discharge, then – in 1, 3, 6 months. Supervision should be stopped in case of complete
recovery of the patient after 6 mo of dispensaryzation;
• physical education should be restriced on 3-6 months, sports on 12 months.
Long-Term Monitoring
Hepatitis B
All persons with chronic Hepatitis B who are not immune to Hepatitis A should receive 2 doses of
Hepatitis A vaccine 6-18 months apart. Infants of HBsAg-positive women should receive Hepatitis B
immunoglobulin and Hepatitis B vaccination within 12 hours of birth, a complete set of 3 vaccinations,
and long-term follow-up.
Reserve routine screening using ultrasonography and alpha-fetoprotein determination for patients
with severe chronic active hepatitis, cirrhosis, or both.
Hepatitis C
Long-term monitoring is essential in patients with chronic HCV infection because the risk of liver
cancer is high, even in sustained virologic responders.
The prothrombin time is useful for assessing
liver function. The serum alpha-fetoprotein assay is a potential screening test for HCC.
Ultrasonography is potentially useful to monitor for Hepatitis C virus–related complications such as
portal hypertension and HCC.
Hepatitis D
Follow-up is recommended for at least 6 months to determine if chronic Hepatitis B virus (HBV)
and Hepatitis D virus (HDV) infection develop.
Perform a liver biopsy to stage liver disease prior to beginning interferon alfa therapy.
Treatment with interferon can be continued after the 1-year period if well tolerated and efficacy is
demonstrated. Monitoring HDV RNA and Hepatitis B surface antigen (HBsAg) levels may help in
guiding therapy.
Prophylaxis of enteral hepatitis
• Early isolation of ill person.
• Supervising contacted, laboratory test every 10-15 days.
• Personal hygiene.
• Disinfection in the epidemic focus.
• Passive prophylaxis by human immune globulin.
• Immunization for the Hepatitis A virus (HAV) infection for patients at risk of the disease. Hepatitis
E is preventable by vaccination (a recombinant genotype 1 HEV vaccine, genotype 4 HEV was
also prevented with the vaccination, indicating cross-protection against different HEV genotypes).
Pre-exposure prophylaxis with HAV vaccine is recommended for persons aged 1 year or older
who are traveling to countries where HAV infection is endemic. If the trip is shorter than 2 weeks, or if
the patient is younger than 1 year, IG should be given. If the trip is longer than 3 months, a larger dose
of IG (0.06 mL/kg) is needed for those who cannot receive the vaccine. Repeat dosing is recommended
if the trip lasts longer than 5 months.
HAV vaccine is currently licensed for use in children aged 12 months or older.
When followed with a second dose 6 months later, the vaccine leads to 100%
seroconversion.
Vaccination in areas of extremely high incidence of infection may only be cost-effective
if prevaccination serology is obtained to target nonimmune individuals.
Prophylaxis of parenteral hepatitis
• Early isolation of ill person.
• Sterilization of medical equipment.
• Passive prophylaxis with human immune globulin.
• For Hepatitis B active prophylaxis: universal vaccination refers to the administration of
recombinant Hepatitis B vaccine to all newborn infants with a birth weight of greater than or equal
to 2000 g
as a part of the routine childhood immunization schedule and to all children younger than
11 or 12 years who have not previously received a vaccine. Rapid (0-, 1-, and 2-mo) and standard
(0-, 1- to 2-, 6-mo) schedules have identical efficacy. Some combination vaccines used in the
routine vaccination schedule result in infants receiving 4 doses of HBV vaccine (eg, at 0, 2, 4, and
6 mo). This is considered acceptable. Ukrainian schedule: within the first 24 hours after birth, in 1,
6 months. For preterm infants who weigh less than 2000 g and are born to mothers with unknown
HBsAg status, 0.5 mL HBIG should be given within 12 hours. When mother is HBs Ag positive –
administer HBIG 0.5 mL intramuscularly with the first dose of recombinant HBV vaccine within
12 hours of birth.
• No vaccine is available for HDV, but the HBV vaccination is effective against HDV.
Key words and phrases: Viral hepatitis, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus,
Hepatitis D virus, Hepatitis E virus, Hepatitis G virus, viral antigens, alanine aminotranspherase, aspartate
aminotranspherase, Carole’s triad, “flu like syndrome”, clay-colored stools, special hepatitis markers,
prodromal period, jaundice period, conjugate bilirubin, bile pigments.
References:
1. USMLE Step 2 CK Lecture Notes 2018: Pediatrics. - Kaplan Medical, 2018. – P. 133-135.
2. USMLE Step 2 CK Lecture Notes 2018: Internal Medicine. - Kaplan Medical, 2018. – P. 248-251.
3. Manual of children's infectious diseases / O. Ye. Fedortsiv, I. L. Horishna, H.A. Pavlyshyn, I. M. Horishniy. -
Vinnytsya: NOVA KNYHA, 2020. - 440 p. - ISBN 978-966-382-814-5.
4. Feigin and Cherry`s Textbook of Pediatric Infectious Diseases, 8
th
Edition, Elsevier, Inc., 2019.- 3992 p. ISBN:
978-0-323-37692-1.
5. Manual of Childhood Infections: The Blue Book, 4
th
Edition (Oxford Specialist Handbooks in Paediatrics) by
Mike Sharland, Andrew Cant and al. Published by Oxford University Press Inc., New York, 2017 , 1035 p.
ISBN: 978-019-872-92-27.
6. Illustrated Textbook of Paediatrics, 5th Edition. Published by Lissauer & Clayden, Elsevier, 2018, 559 p.
ISBN: 9780723438724.
7. Nelson Textbook of Pediatrics, 2-Volume Set, 21st Edition. Kliegman, Geme. Published by Jenson & Stanton,
Elsevier, 2019, 4264 p. ISBN: 9780323568890.
8. Oxford Textbook of Medicine: Infection by David Warrell, Timothy M. Cox, John Firth and Mili Estee Torok,
Published by Wiley-Blackwell, 2012, 900 p. ISBN:
978-0199652136.
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