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1. Hepatitis By Okechukwu Adaora A. Professor/ Honorary Consultant, University of Abuja/ University of Abuja Teaching Hospital, Gwagwalada

2. Outline Introduction Features of Hepatotrophic viruses Causes of Hepatitis in Children Pathogenesis Biochemical Profiles in Acute Infectious Phase Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Other Viruses Causing Hepatitis Hepatitis F, G, TT, Cytomegalovirus (CMV), Ebstein Bar Virus (EBV), Herpis Simplex Virus (HSV)

3. Introduction Viral hepatitis continues to be is a major health problem in both developing and developed countries. This disorder is caused by at least 5 pathogenic hepatotropic viruses. H epatitis A, B, C, D, and E viruses. Many other viruses (and diseases) can cause hepatitis, usually as component of a multisystem disease. These include herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus, HIV, rubella, adenoviruses, enteroviruses, parvovirus B19, and arboviruses

4. Features of Hepatotrophic Viruses H epatotropic viruses are heterogeneous group of infectious agents that cause similar acute clinical illness. In most pediatric patients, the acute phase causes no or mild clinical disease. Morbidity is related to rare cases of acute liver failure (ALF) from it. This is triggered in susceptible patients, to the chronic disease state, and attendant complications that are common to three of these viruses ( hepatides B, C, and D).

5. Features of Hepatotrophic viruses Contds VIROLOGY HAV RNA HBV DNA HCV RNA HDV RNA HEV RNA Incubation (days) 15-19 60-180 14-160 21-42 21-63 Transmission Parenteral Rare Yes Yes Yes No Fecal-oral Yes No No No Yes Sexual No Yes Yes Yes No Perinatal No Yes Rare Yes No Chronic infection No Yes Yes Yes No Fulminant disease Rare Yes Rare Yes Yes

6. Causes of Hepatitis In Children Infectious Causes: Hepatotropic Viruses HAV HBV HCV HDV HEV Hepatitis non-A-E viruses Systemic Infections with Hepatitis Adenovirus Arbovirus Coxsackievirus Cytomegalovirus Enterovirus Epstein-Barr virus “Exotic” viruses (e.g., yellow fever) Herpes simplex virus Human immunodeficiency virus Paramyxovirus Rubella Varicella zoster Others

7. Other Causes of Hepatitis In Children Non-Viral Hepatitis Abscess, Amebiasis , Bacterial sepsis Brucellosis (caused by aerobic, non–spore-forming, non-motile , gram-negative cocco -bacilli ) Fitz-Hugh-Curtis syndrome (Dissemination of gonococcal infection from fallopian tubes through peritoneum to liver capsule resulting in perihepatitis ) Histoplasmosis ( caused by Histoplasma capsulatum , a dimorphic fungus found in the environment ) Leptospirosis ( caused by spirochetes of the genus Leptospira ) Tuberculosis Others Autoimmune Autoimmune hepatitis Sclerosing cholangitis S ystemic lupus erythematosus, J uvenile rheumatoid arthritis Metabolic α1- Antitrypsin deficiency Tyrosinemia Wilson disease Other

8. Other Causes of Hepatitis Contds Toxic Iatrogenic or drug induced (e.g., acetaminophen) Environmental (e.g., pesticides) Anatomic Choledochal cyst Biliary atresia Others Haemodynamic Shock Congestive heart failure Budd-Chiari syndrome Other Non-alcoholic Fatty Liver Disease Idiopathic Reye syndrome

9. Common Features of All Forms of Viral Hepatitis C linical icterus, c ould be mixed or conjugated (direct) hyperbilirubinemia I cteric skin and mucous membranes is common. Tender hepatomegaly S plenomegaly and lymphadenopathy may be present. Extrahepatic symptoms common in HBV and HCV I nclude rashes, arthritis. A ltered sensorium and hyper- reflexibity should be carefully sought This m arks the onset of encephalopathy and acute liver failure (ALF).

10. D ifferential D iagnosis Varies with age of presentation. In the newborn period, c ommon causes of conjugated hyperbilirubinemia, B acterial agent are E coli, Listeria, Syphilis, n on- hepatotropic viruses (HSV, enteroviruses, CMV). Metabolic causes ( tyrosinemia ) A natomic causes b iliary atresia, G enetic forms of intrahepatic cholestasis, and choledochal cysts.

11. Differential diagnosis Contd In later childhood, E xtrahepatic obstruction (gallstones, primary sclerosing cholangitis, pancreatic pathology), I nflammatory causes (autoimmune hepatitis, juvenile rheumatoid arthritis, Kawasaki disease, immune dysregulation), I nfiltrative disorders (malignancies), T oxins and medications, M etabolic disorders (Wilson disease, cystic fibrosis), I nfection (EBV, varicella, malaria, leptospirosis, syphilis).

12. Pathogenesis Acute response of liver to hepatotropic viruses involves: Cytopathic and immune-mediated injury. Centrilobular necrosis Mixed inflammatory infiltrate in the portal areas and the lobules. Lobular architecture remains intact, Balloon degeneration and necrosis of single or groups of parenchymal cells. Fatty change is rare except with HCV infection. Bile duct proliferation common. Diffuse Kupffer cell hyperplasia in the sinusoids. Giant cells formation in neonates .

13. Pathogenesis Contds In Fulminant Hepatitis: Parenchymal collapse occurs. With recovery, the liver morphology returns to normal within 3  mo of acute infection. If chronic develops, the inflammatory infiltrate settles in the periportal areas often leading to progressive scarring. Both hallmarks of chronicity are seen in HBV and HCV

14. Biochemical Profiles in Acute Infectious Phase 3 Main F unctional L iver B iochemical P rofiles Cytopathic injury: ↑ A lanine aminotransferase (ALT ), ↑ A spartate aminotransferase (AST ). Magnitude does not correlate with the extent of hepatocellular necrosis and has little prognostic value. Cholestasis: ↑ S erum conjugated bilirubin levels , from abnormal bile flow due to hepatocyte damage and inflammatory mediators.

15. 3 Main Functional Liver Biochemical Profiles Contds Altered synthetic function : Prolonged prothrombin time High international normalized ratio [INR], Low serum albumin levels Hypoglycemia, lactic acidosis, hyperammonemia Poor clearance of medications dependent on liver function, and Altered sensorium with increased deep tendon reflexes

16. Hepatitis A Hepatitis A virus (HAV) infection is the most prevalent of the 5 hepatotrophic viruses. Is responsible for most acute and benign hepatitis F ulminant form is rare. Etiology HAV is an RNA virus , A member of the picornavirus family. Is heat stable with limited host range, human and other primates.

17. Hepatitis A Virus

18. Epidemiology of HAV Most prevalent in developing countries. O utbreaks common in daycare centers from non-icteric , infected children. F oodborne and waterborne outbreaks are common. H ighly contagious, transmission by person-to-person from fecal-oral route. No other form of transmission is recognized. Perinatal transmission occurs rarely, Mean incubation period is ∼3 wk. Fecal excretion of the virus starts late in the incubation period , Peak b4 onset of symptoms , Resolves 2  wk after the onset of jaundice. Patient contagious b4 clinical symptoms until viral shedding ceases.

19. Clinical Manifestations of HAV Responsible for only acute hepatitis, and o ften anicteric. S ymptomatic in older adolescents or adults , patients with liver disorders, and immunocompromised individual. Is an acute febrile illness with abrupt onset of anorexia, nausea, malaise, vomiting, and jaundice. D uration of illness is 7-14 days Regional lymph nodes and the spleen may be enlarged. The bone marrow may be moderately hypoplastic , with aplastic anemia. There are changes in villous structure, and ulceration of GIT in fatal cases . Acute pancreatitis and myocarditis can occur though rarely N ephritis , arthritis, vasculitis, and cryoglobulinemia from circulating immune complexes

20. Diagnosis Detection anti-HAV IgM by radioimmunoassay I dentifying viral particles in stool. Neutralizing anti-HAV IgG is detected within 8  wk of symptom onset. Anti-HAV (IgG) confers long-term protection . Treatment There is no specific treatment. Supportive treatment with IV hydration Antipruritic agents F at-soluble vitamins for the prolonged cholestatic form of disease. Serial monitoring of ALF

21. Complications ALF rare but not infrequent complication of HAV. A t risk are: A dolescents, A dults, U nderlying liver disorders, and I mmunocompromised . In endemic areas, it constitutes 40% of all cases of pediatric ALF. Prolonged cholestatic syndrome that waxes and wanes over several mths . Pruritus & fat malabsorptn to support with antipruritic and fat-soluble vits .

22. Prevention HAV infected person is contagious for 2  wk b4 & 7 days after the onset of jaundice & should be excluded from school, child care, or work during this period. Handwashing after changing diapers & before preparing or serving food. In hospital settings, contact and standard precautions are recommended. IG: IM (IG) (0.02 mL/kg) for pre & post-exposure prophylaxis Prognosis: Excellent, with no long-term sequelae, The only feared complication is ALF

23. Hepatitis B (HBV) Etiology A member of hepadnaviridae family, a circular, partially double-stranded DNA W ith approx designated hepatitis B surface antigen (HBsAg), A 22 nm diameter spherical & tubular particle with variable length of 3,200 nucleotides. Four genes identified: S (surface), C (core), X, and P (polymer) genes. The inner portion of the virion contains The core antigen ( HBcAg ), T he nucleocapsid that encodes the viral DNA, and A nonstructural Ag called hepatitis B e antigen ( HBeAg ), derived from HBcAg by proteolytic self-cleavage. HBeAg serves as marker of active viral replication & correlates with HBV DNA levels. Replication of HBV occurs predominantly in the liver but also occurs in the lymphocytes, spleen, kidney, and pancreas.

24. HEPATITIS B VIRUS

25. Epidemiology of HBV Worldwide distribution, over 400 million persons chronically infected. Highest in sub-Saharan Africa, China, parts of Middle East , Amazon basin, and Pacific Islands. Present in high concentrations in blood, serum, and serous exudates, M oderate concentration in saliva, vaginal fluid, and semen. Transmission MOSTLY through blood exposure & sexual contact. Risk include: IV drugs users or Blood products, A cupuncture or tattoos, S exual contact, I nstitutional care, & I ntimate contact with carriers.

26. Epidemiology of HBV Contds Not transmitted via indirect exposure such as sharing toys. Perinatal exposure to HBsAg -positive mother remain the greatest risk in children, especially those who are also HBeAg positive. Immuno-prophylaxis of those infants is very effective in preventing infection Breast-feeding of non-immunized infants by infected mothers does not confer a greater risk than does formula feeding. The risk of developing chronic HBV infection, defined as being positive for HBsAg for >6  mo , is inversely related to age of acquisition

27. Pathogenesis HBV is a non-cytopathogenic virus causing injury by immune-mediation. C omplete immune response with viral clearance has most severe liver injury. The first step in acute infection is the expression of viral antigens (HBcAg and HBeAg) on the cell surface of the hepatocytes. The mechanism for the development of chronic hepatitis is less well understood. The tolerance phenomenon in HBV infection predominates I n acquired perinatal infections, with high incidence of persistent infection and little or no inflammation in the liver. The risk of hepatocellular carcinoma is very high from uncontrolled viral replication. Immune-mediated mechanisms are also involved in the extrahepatic conditions .

28. Clinical Manifestations of Acute HBV Many acute cases are asymptomatic, Symptoms similar to that of HAV and HCV infections More likely to involve the skin and joints. F irst biochemical evidence is ↑ ALT levels , before: D evelopment of fatigue, anorexia, & malaise, which occurs about 6-7  wk after exposure . Serum sickness–like prodrome of arthralgia or Skin lesions, urticarial , purpuric, macular, or maculopapular rashes may precede symptoms. Other extrahepatic conditions include: Polyarteritis , Glomerulonephritis , and Aplastic Anaemia Jaundice is present in 25 % of acutely infection. Most patients recover, but the “chronic carrier state” complicates up to 10% of cases acquired in adulthood.

29. Clinical Manifestations of Chronic HBV Chronicity depends on the mode and age of acquisition . Up to 90% in the perinatal cases . Chronic hepatitis, cirrhosis, & hepatocellular carcinoma seen with chronic infection . Has 3 identified phases : I mmune tolerant, I mmune active, and I nactive . In the immune‐tolerant phase , The host immunity against HBV is weak . The viral load is high. AST/ALT is low because there is no attack on the infected hepatocytes by the weak host immune system . Most children fall in this phase with no effective therapy . Spontaneous HBeAg seroconversion occurs in this phase at low rates of 4-5% per year.

30. Clinical Manifestations of Chronic HBV Contds Immune active phase Characterized by active inflammation, elevated ALT/AST, and progressive fibrosis . H ost immunity become strong and infected hepatocytes are attacked, and AST/ALT increases More common in childhood-acquired HBV rather than in vertically transmitted infections. Seroconversion can last many years, during which significant damage to the liver can happen . Immune inactive phase Chronic HBV infection evolves at least for 6 months , Associated with normal ALT, U ndetectable or very low serum HBV DNA levels below 2000 IU/ml, HBeAg negative,  Reactivation of chronic infection has been reported in immunosuppressed children leading to increased risk of ALF or to rapidly progressing fibrotic liver disease

31. Diagnosis Several Ag and Ab are used to confirm the diagnosis of acute HBV infection.sdd Routine screening requires ≥3 markers: HBsAg, anti- HBc , anti-HBs, HBeAg HBsAg is the first marker to rise coincides with the onset of symptoms. Persistence of HBsAg beyond 6  mo defines the chronic infection. IgM antibody to HBcAg (anti- HBc IgM) might be the only marker of acute infection. Remains positive for m ths b4 replaced by anti- HBc IgG, which persists for yrs.

32. Diagnosis Contds Anti- HBc is a valuable serologic marker of acute HBV infection. Anti-HBs marks recovery and protection, & present in immunized person. Both anti-HBs and anti- HBc are detected in persons with resolved infection. HBeAg is present in active acute or chronic infection and is a marker of infectivity. Development of anti- HBe marks improvement, & goal of therapy in chronically infected. HBV DNA can be detected in acutely infected and chronic carriers. High DNA titers seen in patients with HBeAg , and fall once anti- HBe develops.

33. Complications ALF with coagulopathy, encephalopathy, & cerebral edema. R isk of ALF ↑ ed with HDV co-infection & in immunosuppressed host . Mortality from ALF is >30 %, liver transplantation is the only effective intervention. HBV infection can also result in chronic hepatitis, which can lead to cirrhosis, end-stage liver disease, & primary hepatocellular carcinoma ( HCC ). Membranous glomerulonephritis is a rare complication.

34. Treatment Treatment of acute HBV infection is largely supportive. Close monitoring for liver failure and extrahepatic morbidities is key. Treatment of chronic HBV infection: The goal of treatment is to reduce viral replication as defined by undetectable HBV DNA and development of anti- HBe . This seroconversion transforms the disease into an inactive form, By decreasing active liver injury and inflammation, fibrosis progression, and infectivity as well as the risk of HCC. Currently, treatment is only indicated for patients in the immune-active form of the disease.

35. Treatment Strategies Interferon-α-2b (IFN-α2b ): given subcutaneous has immunomodulatory and antiviral effects. Duration of treatment for 24 weeks, and possible side effects (marrow suppression, depression, retinal changes, autoimmune disorders). Lamivudine is an oral synthetic nucleoside analog that inhibits the viral enzyme reverse transcriptase. In children >2  yr , its use for 52  wk resulted in the emergence of a mutant viral strain (YMDD ) a barrier to its long-term use. Adefovir (a purine analog) is approved for use in children >12  yr of age. Peginterferon -α2 and several new nucleotide/nucleoside analogs ( Telbivudine , Tenofevir , and Entecavir ) are approved for use in adults. Has less viral resistance than IFN-α2b or Lamivudine in the adult population. Immuno-tolerant patients are currently not considered for treatment.

36. Prevention Hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) are available for prevention of HBV infection. Household , sexual, and needle-sharing contacts should be vaccinated if they are susceptible to HBV infection. HBV is not spread by breast-feeding, kissing, hugging, or sharing water or utensils . HBIG is indicated only for specific post-exposure circumstances and provides only temporary protection. It plays a pivotal role in preventing perinatal transmission when administered within 12 h of birth.

37. Hepatitis C (HCV) Etiology HCV is a single-stranded RNA virus , within the Flaviviridae family, with marked genetic heterogeneity. It has 6 major genotypes and numerous subtypes and quasi-species, which permit the virus to escape host immune surveillance. Epidemiology T he most common cause of chronic liver disease in adults Seroprevalence is 0.2% in children <11  yr , and 0.4 % ≥11  yr in USA. Risk factors include: Blood transfusion, Illegal drug use with exposure to blood or blood products from infected persons, sexual transmission. Perinatal transmission is the most prevalent mode of transmission in children. HIV co-infection and high viremia in mother ↑ es transmission rate to 20%. The incubation period is 7-9  wk (range, 2-24  wk ).

38. Pathogenesis The pattern of acute hepatic injury is indistinguishable from that of other hepatotropic viruses. In chronic cases, lymphoid aggregates or follicles in portal tracts are found. Steatosis is also often seen in these liver specimens. HCV appears to cause injury primarily by cytopathic mechanisms, but immune-mediated injury can also occur . The cytopathic component appears to be mild, because the acute illness is typically the least severe of all hepatotropic virus infections . Clinical Manifestations Acute HCV infection tends to be mild and insidious in onset. ALF rarely occurs . HCV is the most likely hepatotropic virus to cause chronic infection. In pediatric studies, 6-19 % can achieve spontaneous clearance of the virus.

39. Clinical Manifestations Contds Chronic HCV infection Is also clinically silent until a complication develops . Serum aminotransferase levels fluctuate and are sometimes normal, but histologic inflammation is universal . Progression of liver fibrosis is slow for several years , comorbid accelerate it. 25% progress to cirrhosis, liver failure , primary HCC within 20-30  yr of acute infection . The long-term morbidities constitute the rationale for treating children with HCV.

40. Clinical Manifestations Contds Extrahepatic manifestations include: S mall vessel vasculitis, M ixed cryoglobulinemia , C utaneous vasculitis, P eripheral neuropathy, C erebritis , Membrano -proliferative glomerulonephritis, and N ephrotic syndrome. Antibodies to S mooth muscle, A ntinuclear antibodies, and L ow thyroid hormone levels may also be present

41. Diagnosis Detection of Ab to HCV Ag or viral RNA. PCR detects HCV RNA in serum and tissue samples. Risk group for screening include: I llegal drug use, R eceiving clotting factors or blood products, H emodialysis, Idiopathic liver disease, and C hildren born to HCV-infected mothers. HCV genotyping : Genotype 1 responds poorly to tx , genotypes 2 and 3 responds better. Aminotransferase level do not correlate with the degree of liver fibrosis. L iver biopsy assess the presence and extent of hepatic fibrosis. I ndicated only b4 starting tx to rule out other causes of liver disease .

42. Treatment of HCV Infection Peginterferon IFN-α2b, and oral ribavirin is used in children >3  yr. G oal of tx is to achieve a sustained viral response (SVR ), defined as absence of viremia 6  mo after stopping medications Factors associated with a higher response include: Age <12  yr , G enotypes 2 and 3, and, P atients with genotype 1b, RNA titer <2 million copies/mL V iral response (PCR at weeks 4 and 12 of treatment ). Side effects of medications include: Anemia , N eutropenia , and I nfluenza-like symptoms . Newer Treatments Peginterferon and an antiviral telaprevir . Studies are pending in pediatrics.

43. Complications of HCV The risk of ALF is low Risk of chronic hepatitis is highest of all the hepatotropic viruses . Prevention No vaccine is available to prevent HCV, IG preparations are not beneficial ,. Y early screening with liver ultrasound, α-fetoprotein for HCC, & clinical evidence of liver disease. Vaccination against HBV to prevent super-infection that will ↑ risk of developing severe liver failure . Prognosis Viral titers should be checked yearly to document spontaneous remission. Most patients develop chronic hepatitis . Progressive liver damage is higher in those with additional comorbid factors such as alcohol consumption, viral genotypic variations, obesity, and underlying genetic predispositions .

44. Hepatitis D Etiology HDV is the smallest known animal virus Considered defective bcos it cannot produce infection without concurrent HBV infection. The 36  nm virus is incapable of making its own coat protein Its outer coat is composed of excess HBsAg from HBV. The inner core is single-stranded circular RNA that expresses the HDV antigen . Epidemiology HDV can cause infection at the same time as the initial HBV infection (co-infection), or HDV can infect a person who is already infected with HBV (super-infection). Transmission occur by intimate contact in areas of high prevalence in developing countries. In areas of low prevalence parenteral route is more common . The incubation period for HDV super-infection is about 2-8  wk ; W ith co-infection , incubation period is similar to that of HBV infection .

45. Pathogenesis Liver pathology in HDV hepatitis has no distinguishing features except that damage is usually quite severe . In contrast to HBV, HDV causes injury directly by cytopathic mechanisms. Many of the most severe cases of HBV infection appear to be a result of co-infection of HBV and HDV.

46. Clinical Manifestations of HDV Symptoms similar to but more severe than other hepatotropic viruses. C linical outcome depends on the mechanism of infection. In co-infection: a cute hepatitis more severe than HBV alone , chronic hepatitis is low . In super-infection : a cute illness is rare, and chronic hepatitis is common. R isk of ALF highest in super-infection, to be considered in any child who with ALF . Diagnosis B y detecting IgM antibody to HDV Ab develops 2-4   wk after co-infection and ∼10  wk after a super-infection . PCR assays for viral RNA is research tools. Complications C onsidered in all cases of ALF. Co-infection with HBV can also result in a more severe chronic disease .

47. Treatment Treatment is supportive. Based on controlling and treating HBV infection, without which HDV cannot induce hepatitis . Prevention N o vaccine for hepatitis D. Because HDV replication cannot occur without hepatitis B co-infection, immunization against HBV also prevents HDV infection. Hepatitis B vaccines and HBIG are used for the same indications as for hepatitis B alone.

48. Hepatitis E Etiology HEV has not been isolated but has been cloned using molecular techniques. This RNA virus has a non-enveloped sphere shape with spikes.

49. Hepatitis E Epidemiology Formerly called non-A, non-B hepatitis. Transmission is fecal-oral (often waterborne) and is associated with shedding of 27-34 nm particles in the stool. Highest prevalence seen in Indian, Middle East, Southeast Asia, and Mexico, especially in areas with poor sanitation. The mean incubation period is approx. 40 days (range, 15-60 days). Pathogenesis A ct as a cytopathic virus. Pathologic similar to other hepatitis viruses .

50. Clinical Manifestations S imilar to HAV but more severe. As with HAV, chronic illness does not occur . O ften causes a more severe episode than HAV, T ends to affect older patients, with a peak age between 15 and 34  yr A major pathogen in pregnant women, in whom it causes ALF with a high fatality incidence . C ould also lead to decompensation of pre-existing chronic liver disease . Complications HEV is associated with a high risk of death in pregnant women . No other complications are recognized in association with this virus.

51. Diagnosis IgM antibody to viral antigen becomes positive after ∼1  wk of illness. Viral RNA can be detected in stool and serum by PCR . Prevention A recombinant hepatitis E vaccine is highly effective in adults . Immunoglobulin not effective in preventing HEV infections.

52. Other Viruses Causing Hepatitis Hepatitis F Not much known about this virus, discovered in patients with fulminating hepatic failure. Hepatitis G Three groups known, GBV-A, GBV-B, GBV-C. Seen in patients with fulminating hepatic failure, clinical hepatitis, haemophilias , multi-transfusion patients and patients on maintance dialysis. Hepatitis TT Associated with acute and chronic liver diseases of unknown etiology. Is a DNAvirus that does not seem to cause any exacerbate liver damage.

53. Other Viruses Causing Hepatitis Cytomegalovirus(CMV) Has worldwide distribution Perinatal, person to person, and blood transfusion are the mode of transmission Spectrum of illness include : asymptomatic, subclinical, febrile systemic illness, atypical mononucleosis, Gullian Barre’s syndrome, and frank hepatitis The jaundice may persist for 1 month, and liver test is abnormal Herpes Simplex Virus (HSV) Mostly encountered in neonates and immunocompromised individuals Characterised by fever, mild to moderate hepatomegaly, and Pronounced elevation of transaminases

54. Other Viruses Causing Hepatitis Ebstein Bar Virus (EBV) Implicated in the cause of infectious mononucleosis in young adults Strongly associated with Burkitts Lymphoma. Transmission occur by blood transfusion, and intimate personal contact Clinical presentation is mild jaundice, anorexia, abdominal pain, hepatomegaly and elevated liver enzymes

55. References Nada  Yazigi , William F.  Balistreri. Viral Hepatitis: In Nelson Textbook of Pediatrics, Nineteenth Edition, 2021, by Saunders, an imprint of Elsevier Inc. Philadelphia, USA . Yakubu AM. The Liver and the Gallbladder. In Paediatric and Child Health in Tropical Region. 2nd Edition. Azubuike and Nkanginieme . African Educational Services, Owerri , Nigeria.

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