Tuesday, February 26, 2013

Viral Hepatitis: All You Need To Know For Proper Prophylaxis And Prevention




Acute hepatitis is a continuing hepatic inflammatory process manifested by elevated hepatic transaminase level, lasting less than 6 mo and accompanied with pain, dyspeptic, intoxication and cholestatic syndromes

Etiology               
·        HAV is RNA-containing virus 27-30 nm in diameter;
·        HBV is DNA-containing virus from HepaDNA viruses family of, 42 nm in diameter;
·        HCV is virus 22-60 nm in diameter, probably flavivirus family;
·        HDV is virus 35-37 nm in diameter with small RNA and HB virus shell;
·        HEV is virus-like particle of spherical form 27 nm in diameter;
·        HGV, HFV, TTV – viruses are insufficiently known.

Epidemiology:
Source of infection – carries of viruses, ill person;
Way of spreading – alimentary for HAV and HEV;
parenteral and vertical, sexual, micro traumas for HBV, HCV, HD, HFV and TTV; Susceptibility is high.

HAV, HEV      
ü       the source is a patient with typical and atypical forms of infection, and viral carrier;
ü       the mechanism of transmission is fecal-oral, usually realized by the contaminated food, water and by direct contact;
ü       receptivity - HAV 70-80 % (children elder than 1 year), HEV is probably high.
HBV, HCV, HDV
ü       source - viral carriers, patients with acute and chronic  forms;
ü       mechanism of transmission:  
ü       parenteral;
•  vertical (transplacental, at breast feeding);
•  sexual (micro trauma);
•  domestic (micro trauma);
ü       receptivity is the greatest at children of early age, people elder than 30 years.

Pathogenesis:
Hepatitis A, E
1.     Inoculation of the pathogen (entrance gate – small intestine).
2.     Viremia.
3.     Viral fixation on hepatocytes, intracellular localization.
4.     Primary replication of the virus.
5.     Excretion with a goal to intestine.
6.     Part of the viruses caused viremia (prodromal period of the disease).
7.     Activation of immune system, that causes cytolysis, mesenchimal inflammation and cholestasis.
8.     Immune response, elimination of the virus.
Hepatitis B
1.     Inoculation of the pathogen.
2.     Viremia.
3.     Viral integration and replication in hepatocytes, also may be in blood cells, bone marrow, lymph nodes, spleen.
4.     Activation of immune system, that causes cytolysis, mesenchimal inflammation and cholestasis.
5.     Immune response, elimination or persistence of the virus.
Hepatitis C
1.     Inoculation of the pathogen.
2.     Viremia.
3.     Viral integration and replication in hepatocytes, also may be in blood cells, bone marrow, lymph nodes, spleen.
4.     Activation of immune system with low immune response.
5.     Mutation changeability of the virus.
6.     Persistence of the virus.
Hepatitis D
Need virus hepatitis B for its replication, develops only in infected HBV patients.

 

Classification
Type:          -
ü     typical (jaundice);
ü     atypical
§        without jaundice (unicteric hepatitis);
§                       effaced;
§        subclinical hepatitis.
§        Cholestatic hepatitis
§        Fulminant hepatitis
Severity:     
ü     mild
ü     moderate
ü     severe
Course:
ü    acute (2-3 months);
ü    prolonged (3-6 months);
ü    chronic.
        
Periods:     
         Incubation
         Pre-icteric
         Icteric
         Post-icteric
         Convalescent

Diagnostic criterions of incubation period

·        absence of clinical signs
·        viral antigens are present in blood
·        alanine aminotranspherase, aspartate aminotranspherase may be enlarged.

Prodromal (prejaundice, preicteric) period

·        headache
·        rashes (often in HBV-hepatitis)           
·        Arthralgias                                         Carole’s triad
·        "flu like syndrome"
·        dyspepsia
·        hepatomegaly, pain in right costochondrial rib, epigastrium
·        in the end – appearing of clay-colored stools
·        Enlargement of ALAT and ASAT, urobilinuria, special hepatitis markers.

  

Jaundice (icteric) period

·        Jaundice of mucous membranes, sclera, and skin (photo).
·        Urobilinuria, bilirubinuria.
·        Hepatomegaly (photo), tenderness of liver.
·        ALAT and ASAT are maximally enlarged.
·        Hyperbilirubinemia with conjugate bilirubin prevalence.
·        skin rashes
·        hemorrhagic syndrome
·        splenomegaly

Laboratory tests
Prodromal period
·        Enlargement of ALAT and ASAT, urobilinuria.
·        Anti-HAV Ig M, HAV-RNA (hepatitis A).
·        HBsAg, HBeAg, HBV-DNA and anti-НВс IgM (hepatitis B).
·        HBsAg, HBeAg, HBV-DNA, anti-НВс IgM and HDVAg, HDV-RNA (hepatitis delta coinfection).
·        HCV-RNA (hepatitis C).
·        Anti-HEV Ig M, HEV-RNA (hepatitis E).

Jaundice period

 Nonspecific tests

·        enlargement of ALAT and ASAT ,
·        hyperbilirubinemia with conjugate bilirubin prevalence,
·        marking  of bile pigment in urine,
·        increased sediment tymol test
·        decreased sulemic test (severe hepatitis B)
·        decreased prothrombine index, fibrinogen
·        in cholestasis alkaline phosphatase, cholesterol, GGTP are increased
 Specific tests (markers)
·        Anti-HAV Ig M, HAV-RNA (hepatitis A).
·        HBsAg, HBeAg, HBV-DNA and anti-НВс IgM (hepatitis B).
·        HBsAg, HBeAg, HBV-DNA, anti-НВс IgM  and HDVAg, anti-HDV IgM, HDV-RNA.(hepatitis delta coinfection)
·        HCV-RNA, anti-HCVcore IgM and IgG (acute hepatitis C).
·        Anti-HEV Ig M, HEV-RNA (hepatitis E).







Severity criterions (in icteric period)

Signs
Mild
Moderate 
Severe 
Degree of intoxication in preicteric period, body temperature
mildshortsubfebrile
Moderate, t 38-39 °С (in preicteric period)
Severe, t° 39 and more
Jaundice
mild
Mild-to moderate
severe
Liver size increases
Up to 2 сm
On 2-5 см
More than 5 см
Bilirubin increase
indirect bilirubin increase
Up to 85 mcmol/l
Up to 25
85-200
25-50
> 200
> 50
Aminotranspherases level
5-10 times more than norm

10-15 times more than norm
15-30 times more than norm
Protrombin index
70-80 %

60-70 %
< 60%
Tymol test
Mild increased
moderately increased
Very increased
Normalization of the liver sizes
On 25-35 day from the beginning
On 40-50 day
On 50-60 day
When the jaundice appears the toxic sign
Decreased
Continue for 2-3 days

continuesometimes increases
splenomegaly
––
In 1.5 %
Is typical
Diuresis
normal
decreased
Severe decreased
Sulemic test
normal
normal
decreased
Duration of icteric phase
7-10 days
1-2 wks
2-3 wks

Posticteric period
·   Urine becomes lighter
·   Stools darker
·   Jaundice fades
·   Decreasing ALAT, ASAT
·   Decreasing of the liver sizes
·        Normalization of bilirubin,  ALAT and ASAT, other indexes, later - sediment tymol test
·        Anti-HAV Ig G, HAV-RNA (hepatitis A).
·        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).

Fulminant form criteria:
ü     Acute failure of the liver
ü     Confusion and drowsiness
ü     Delirium and convulsions
ü     Liver gets smaller
ü     Coma I-II ESG is abnormal
ü     Hepatic smell
ü     Hemorrhagic syndrome
ü     Encephalopathy
ü     Decreasing of diuresis
ü     Total bilirubin  is increased
ü     Protrombin time is prolonged
ü     Decreasing  of ALAT, ASAT
ü     Decreasing of proteins

Atypical (unicteric, effaced, subclinical) forms criteria:
ü     Contact with patient who had hepatitis
ü     Hepatomegaly
ü     increasing  of ALAT, ASAT, tymol test

Outcome of disease
For HAV, HEV
ü                              Recovering
ü                              Residual fibrosis of liver (posthepatitis hepatomegaly)
ü                              Biliary dyskinesia
ü                              Chronic cholecystitis and cholecystocholangitis
 For HBV, HCV , HDV
ü                              Recovering
ü                              Residual fibrosis of liver (posthepatitis hepatomegaly)
ü                              Biliary dyskinesia
ü                              Chronic cholecystitis and cholecystocholangitis
ü     transition in chronic hepatitis;
ü     cirrhosis
ü     hepatic carcinoma
ü                              death.

Diagnosis example: Hepatitis A, typical form, icteric period, mild severity, acute course

Differential diagnosis
Prejaundice period:
ü                         viral upper respiratory tract infections,
ü                         bowel infection,
ü                         acute appendicitis,
ü                         diseases caused by parasites,
ü                         acute pancreatitis.
Jaundice period:
ü                         suprahepatic icterus (hemolytic anemia),
ü                         hepatic icterus (Gilbert, Krigler-Nadjar syndrome, infectious mononucleosis, leptospirosis, pseudotuberculosis, congenital liver diseases, ),
ü                         subhepatic icterus (mechanical jaundice).

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
wks. - 3 mo.
15-45 days
wks. - 6 mo.
Початок хвороби
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.wks

wks

1-2 wks

2-8 wks
transition in chronic hepatitis
Often - primary chronic

––

in 50 %

––

often
Tymol test
Often normal
elevated
Moderately elevated
high
Moderately elevated
Specific markers
HBsAg
HBeAg
anti НВс IgМ
anti HAV
IgМ
anti HCV
РНК HCV
anti HEV
HBsAg, anti НВс,anti HDV IgМ.

Treatment:
Basic treatment:
ü           bed regimen up to intoxication disappear,
ü           half-bed regimen (up to icterus disappear, normalization of ALAT, ASAT)
ü           special diet (diet N 5),
o                    Exclude heavy fats (like pork), spices, fried foods, "fast food"”; avoid stimulators of gastrointestinal secretions, 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.
o                    Foods boiled, steamed and baked are recommended; food taking 5 times daily

Treatment of mild hepatitis – only basic therapy

Treatment of moderate hepatitis
ü                              basic therapy
ü                              peroral detoxication 40-50 ml/kg with water balance control
ü                              enterosorption 1-2 wks (in case of cholestatic variant)
ü                              choleretics from the 3-d week of disease
                      cholagon
                      allocholum
                      cholenzym
                      galstena
                      hepabene

Treatment of severe 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,
• prednizone (in possibility of fulminant form development) and for infants before 1 year with unfavorable 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.

Treatment of fulminant form
• straight bed regimen,
• diet N 5a with protein restriction up to 40 %,
• intravenously:
• prednizone 10-15 mg/kg/day divided in 4 equal doses,
• detoxication therapy (total – 50-100 ml/kg/day) with diuresis control:
• 0.9 % NaCl, Ringer’s solution,
• Ringer’s lactate solution,
• 5 % glucose,
• albumin 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 coagulation factors donator,
• Heparin 100-300 IU/kg in possibility of DIC-syndrome development,
• Protease-inhibitors (trasilol, contrical, gordox) in case of DIC-syndrome development,
• Antibacterial therapy for bacterial complication prevention (less hepatotoxic medicine),
• Enema and stomach-washing,
• Lactulose for 10-14 days.

Discharge from the hospital, supervision, control:
ü     patients with mild and moderate forms can be treated at home;
ü     discharge on 15-20 day of illness with the remaining phenomena (hepatomegaly, slight increased ALAT, ASAT, dysproteinemia);
ü     Finish treatment in dispensary cabinet: first examination - in 7 days, then - in 1, 3, 6 months. In absence of the remaining phenomena - stop dispensarization;
ü      can visit school on 40-50 day, release from physical education on 3-6 months, sport - 12 months

Prophylaxis of A, E hepatitis
·        Early isolation of ill person.
·        Looking after contacts, laboratory test every 10 – 15 days.
·        Personal hygiene.
·        Disinfection in the epidemic focus.
·        Passive prophylaxis by human immune globulin.

 

Prophylaxis of parenteral hepatitis

·        Early isolation of ill person.
·        Sterilization of instrument.
·        Passive prophylaxis by human immune globulin.
For hepatitis B active prophylaxis: after the birth, in 1, 6 months. When mother is HBs Ag positive – after the birth, in 1, 2, 12 months.

 


Key words and phrases: Viral hepatitis, hepatitis A virus, hepatitis B 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:
Main:      
1.      Ambulatory pediatric care/ edited by Robert A. Derchewitz; - 2nd ed. – Lippincot – Raven, 1992. – p. 404-411, P.425-429.
2.      Current therapy in pediatric infections disease – 2/ edited by John D. Nelson, M.D. – B.C. Decker Inc. Toronto, Philadelphia, 1988. – p.74-77, 80-81.
3.      Principles and Practice of Pediatric Infectious Diseases. / Edited by Saran S. Long, Larry K. Pickering, Charles G. Prober, PhiladelphiaPa: Churchill Livingstone; 1997. – 1921 p.

Additional:
1.                         Cleary TG: Yersinia. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia: WB Saunders; 2000: 857-859.
2.                         Pickering L, ed: Yersinia enterocolitica and Yersinia pseudotuberculosis infections. In: Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove VillageIllAmerican Academy of Pediatrics; 2000: 642-643.
3.                         Textbook of Pediatric Nursing.  Dorothy R. Marlow; R. N., Ed. D. –London, 1989.-661p.
4.                         Pediatrics ( 2nd edition, editor – Paul H.Dworkin, M.D.) – 1992. – 550 pp.
5.                         Behrman R.E., Kliegman R.M., Jenson H.B. Nelson nextbook of Pediatrics. - Saunders. - 2004. - 2618 p.
6.                         Castaneda C. Effects of Saccharomyces boulardii in children with Chronic Diarrhoea, Especially Due to Giardiasis // Revista Mexicana de Puericultura y Pediatria. - 1995. - V. 12. - P. 1462-1464.
7.                         Guidelines for control of shigellosis, icluding epidemics due to Shigella type 1/-World Health Organisation, 2005.
8.                         Implementing the New Recommendation on the Clinical Management of Diarrhoea. - World Health Organisation, 2006.
9.                         Klein J.D., Zaoutis T.E. Pediatric Infectious Disease Secrets. - Philedelphia: Hanley & Belfus Inc, 2003. - P. 142.

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