Congenital Hepatic Infections

Congenital Infections

(in the context of Neonatal Hepatitis/Cholestasis)

Bacterial Infections

The reticuloendothelial system of the Liver and Spleen is responsible for clearance of bacteria from the blood. Hepatocellular injury may result from direct infection of hepatocytes and kupffer cells, from circulating/released toxins, or from fever and/or hypoxia. (1) Infants are susceptible to cholestasis during sepsis due to relatively immature bile acid transport mechanisms and changes in regulation which occur during infection. Specific mechanisms are still being elucidated (2) The most common bacterial infection is Urinary tract infection (UTI) and Escherichia coli is the most common pathogen.

UTI

Commonly occur between weeks 2-8 after birth
Clinical manifestations may include:

Lethargy
Irritability
Poor feeding
Occasionally - diarrhea or vomiting
Rarely have fever
Hepatomegaly is frequently reported
Labs show:

Conjugated hyperbilirubinemia
Mild elevation of animotransferases
Leukocytosis with increased neutrophils
UA with pyuria, Cx - E Coli (Bld Cx may be transiently positive as well)

Hepatic pathology is benign (Liver Bx usually unnecessary once UTI is Dx'd)

Non-specific bile stasis
Periportal inflammation
Kupffer cell hyperplasia

Tx with antibiotic therapy specific for Cx result sensitivities

Resolution of Jaundice may be prolonged despite clearance of offending organism (due to formation of bilirubin-protein conjugates in serum)

Consider Galactosemia in all infants with cholestasis/liver disease and gram negative bacterial infections

Congenital Syphilis

Infection with Treponema pallidum from an infected mother can occur anytime during pregnancy or via contact with maternal secretions during or after delivery
Clinical, Labs, Rad findings are due to the inflammatory response to the spirochetes
Consider Syphilis in the Ddx of any neonate with hepatitis
Clinical Manifestations

Neonatal period

Snuffly nose
Hepatosplenomegaly (most common sign - results from extramedullary hematopoiesis)
Lymphadenopathy
Mucosal lesions
Painful bone/cartilage lesions
Erythematous scaly maculopapular rash
Chorioretinitis
+/- Thrombocytopenia or hemolytic anemia
Jaundice may occur within the 1st day of life and mimic erythroblastosis fetalis

Late manifestations (after age 2)

Destructive bone lesions
Saddle nose deformity
Hutchinson Teeth

Confirm infection in mother (if possible)
CBC, LFTs, VDRL, RPR, CSF for cells, protein, and VDRL titer
Compare Venereal disease research laboratory (VDRL) and Rapid Plasma Reagin (RPR) titers with mothers titers

Serology may be positive in normal unaffected infants for up to 3 months after birth due to maternal Antibodies (passively acquired)

Consider imaging if indicated (long bones, neuroimaging, ABR, Eye exam

Liver Bx not necessary, histology would show:

Centrilobular mononuclear infiltrate with extensive fibrosis of the interstitia and of the portal triads surrounding the bile ducts and blood vessels (intralobular dissecting fibrosis) as well as giant cell transformation
Bile duct paucity has been reported
Silver stains on electron microscopy show spirochetes - look in the space of disse and b/w reactive mesenchymal cells

Penicillin G (parenteral)
For PCN allergy, recommend desensitization over alternative antibiotics
Liver disease may be exacerbated by PCN
Resolves slowly

Prognosis

There are not long term sequelae following adequate treatment of congenital syphilis
Serology may remain positive for up to 2 years following appropriate therapy

Tuberculosis

Very Rare
Infection can be acquired by:

Transplacental spread in utero
Perinatally via ingestion/inhalation of anmiotic fluids or maternal secretions
Postnatally from ingestion or inhalation (possibly non-maternal source)

Most pregnant women with TB are asymptomatic - maternal history may not be helpful, most test negative due to anergy assoc w/ pregnancy
Clinial Manifestations

Usualy present after 2wks of age

Fever
Hepatomegaly
Respiratory Sx (Most common)
Rapidly fatal

TB skin test (rarely positive)
CXR
LP
Cx's and fluid for acid fast staining, Cultures, or PCR testing
Liver Bx not needed but would show:

Caseating necrosis with surrounding giant cells and epithelioid cells with tubercle bacilli

Insufficient testing with quantiferon Gold testing to recommend at this time

If suspected and TB skin test negative, prompt treatment with all of the following:

Isoniazid
Pyrazinamide
Rifampin
Streptomycin or kanamycin or amikacin (aminoglycoside)
If TB meningitis present, add corticosteroids

Prognosis

Worse with disseminated disease or with HIV coinfection

Listeriosis

Infection with Listeria monocytogenes can have early (1st day of life) or late onset (>1wk after delivery)
Transplacental infection in utero or at delivery from contact with infected maternal secretions

In Utero infections typically result in premature delivery
Maternal illness usually mild: fever, flu-like Sx, diarrhea

Clinical manifestations

Early onset -usually disseminated with multiple organs involved

May have Rash - erythematous with pale papules (histology reveals granulomas)

Late onset - meningitis
Both always have hepatic manifestations
Hepatomegaly +/- jaundice

Isolation of organisms from blood, mec, CSF, or liver
Liver Bx would reveal

Diffuse hepatitis or miliary microabscesses containing abundant gram-positive rods

Ampicillin and an aminoglycoside (Gentamicin)

Prognosis

30-50% mortality despite therapy

Protozoan Infections

Toxoplasmosis

Infection with the intracellular protozoan parasite Toxoplasma gondii can occur when the organism crosses the placenta infecting the fetus
Maternal infection may be mild - acquired from eating undercooked meat or contact with animal feces - usually cats
Incidence 2-8 per 10,000 liver births
Clinical Manifestations

Neonates may be asymptomatic
Hepatitis may be the only indicator of infection (HSM, +/- Jaundice, +/- Ascites)
Classic Triad:

Chorioretinitis
Intracranial calcifications
Hydrocephalus

Maculopapular rash, purpura
Lymphadenopathy
Thrombocytopenia
Microcephaly
Menigoencephalitis

Prenatal detection of T gondii in fetal blood or amniotic fluid (or from placenta, umbilical cord, or infant peripheral blood) via PCR
IgM or IgA or persistent IgG anti-Toxoplasma Ab test from infants blood (persistes over 12mo)
Liver Bx

non-specific giant cell hepatitis with focal necrosis assoc w/ parasitized sinusoidal cells
Intracellular bile stasis
periportal infiltration
Organism can be seen with fluorescent Ab staining

KUB may show hepatic calcifications in areas of calcified necrosis

Prenatal treatment of mother to prevent in-utero infection with sulfadiazine and pyrimethamine or spiramycin (investigational drug)
Treat infected infants with sulfadiazine and pyrimethamine with folinic acid to prevent hematologic toxicity of treatment

Viral Infections

Cytomegalovirus (CMV)

May be acquired in-utero (transplacentally), during delivery, or postnatally from contact with maternal secretions, breastmilk, or blood transfusion
1-2% of all live births affected, 90% asymptomatic (7.2% will later develop sensorineural hearing loss)
CMV infection should be ruled out in all infants with prolonged cholestasis and infants of mothers who have had liver transplant
Clinical Manifestations

Hepatomegaly - may persist for up to one year
Splenomegaly
Jaundice
Petechiae
Purpura secondary to thrombocytopenia
PNA
Microcephaly
Chorioretinitis
Deafness
Neuro - poor feeding, hypotonia, Seizures (cerebral calcifications)

Complications rare but include: ascites, bleeding diathesis, DIC, secondary bacterial infections, death
Dx:

Culture of nasopharynx, saliva, and urine (urine Cx has better yield than liver culture which can be improved with EM or Viral DNA by PCR, and monoclonal Ab techniques)
Serology can be used ad IgM CMV-specific Ab can be monitored
Liver Bx Histology

Multinucleated giant cell transformation
Large inclusion-brearing cells
Bile stasis
Fibrosis
Bile duct proliferation
Characteristic finding - enlarged cell containing basophilic granules in the cytoplasm and a swollen nucleus. An amphiphilic intranuclear inclusion is surrounded by a clear halo (owl's eye).

Diagnosis confirmed with:

Intranuclear inclusion bodies typically seen in bile duct epithelium and sometimes hepatocytes or kupffer cells

Intracytoplasmic inclusion bodies in hepatocytes

Nuclear and cytoplasmic inclusions represent closely packed virions

Liver calcifications may be found on imaging
If CMV positive, workup should also look for extrahepatic involvement: Fundoscopy, Head US, CT, Hearing eval with brainstem evoked potentials

Ganciclovir for 6wks

May have neuro benefits (reduced rates of hearing loss or other developmental outcomes)
Monitor for neutropenia (seen in 2/3 of patients)
Foscarnet in drug resistant cases (Vlaganciclovir and Cidofovir have also been used in neonates- consider side effects before use)

CMV Ig
Liver Transplant in severe cases

Prognosis

Severe Chronic Liver disease is rare
Poor prognosis with severe infection - Neuro sequelae
In patients with resolution of hepatomegaly, Portal HTN may develop despite not having cirrhosis

Herpes Simplex Virus (HSV)

HSV-2 strains cause more infections; but HSV-1 may have more cases of liver failure
Incidence 1:3200 live births
Premature patients account for up to 50% of cases (chicken or the egg? HSV mothers more likely to deliver prematurely?)
Transmission can occur during delivery by contact with genital tract, ascending infection, or postnatally from caregiver mouth or hands
Most cases, mother has no history or current evidence of infection/ genital lesions
Presentation

Typically 4-8 days of life (coincides with incubation period)
Fulminant presentation with jaundice, hepatomegaly, conjugated hyperbilirubinemia, and elevated transaminases, clotting disorder/bleeding complications
20% will not have typical vesicular rash seen with cutaneous involvement

Histoplogy/Pathology

Generalized or multifocal hepatocyte necrosis and cholestasis with characteristic intranuclear acidophilic inclusion bodies (herpes simplex virions)

intranuclear inclusions are smaller than those of CMV (CMV may have bile duct cell involvement, not seen in HSV)

Multinucleated giant cells may also be present
Varicella-Zoster can produce an identical appearing histology

HSV infection is confirmed with viral culture of skin scrapings from the base of a skin lesion

Can also be detected from conjunctivae, orophayngeal mucosa, stool, urine, and CSF
Direct fluorescent antibody staining or enzyme immunoassay detection of viral antigens
Rapid detection of viral DNA via PCR (CSF >90% positivity in infants with disseminated disease *note: LP not recommended with coagulopathy)

Serology is not helpful due to confounding from maternal Ab
Liver Bx not recommended with coagulopathy

Acyclocir x 3wks via IV
Mortality still 29% with treatment
Liver Transplant in patients with neonatal acute liver failure (NALF) due to HSV

Prognosis

Worse with lack of skin lesions, worse thrombocytopenia and coagulopathy, severe cholestasis, detection of HSV DNA by PCR
Death without treatment

Rubella

Enveloped RNA virus of the Togaviridae family
Clinical Manifestations

Eye (Cateracts, Retinopathy, microphthalmia, Glaucoma)
Cardiac (PDA, Peripheral pulm art stenosis, ASD/VSD)
Auditory (Sensorineural hearing impairment)
Neuro (Behavior, Meningoencephalitis, Mental retardation)
Growth retardation
Radiolucent bone disease
Hepatosplenomegaly (HSM)
Thrombocytopenia
Blueberry muffin skin lesions (hematopoesis in the skin)
Liver

Jandice, HSM, Transient Cholestasis --> late anicteric hepatitis
HSM may continue for over a year

Detection of IgM specific Ab in serum or oral fluid
Viral isolation
Detection of Viral RNA oby PCR of nasopharyngeal swab, blood, or body fluid

Infected neonates may shed rubella virus in nasopharyngeal secretions and urine for up to 1yr and transmit infection to contacts

Liver Bx Histology

Giant Cell Hepatitis
Mononuclear infiltrates of the portal zones with intralobular fibrosis and extramedullary hematopoiesis
Focal areas of necrosis
Bile duct proliferation

Supportive
Infants usually recover

Prognosis

Most complications are due to heart disease and neuro complications
Immunization of prepubertal girls is best for prevention

Enteroviruses

Single Stranded RNA virus of the picornaviridae family include Non-polio enteroviruses:

Coxsackieviruses
Echoviruses
Enteroviruses

Less common
May have maternal history of viral syndrome or fever just before delivery
Clinical Presentation

Wide variety usually poor feeding, fever, lethargy, diarrhea, jaundice and skin rash initiate a sepsis eval
Majority are benign and self limited
Fatal and massive hepatic necrosis, DIC, NALF seen with: Conxsackie group B1-4, enterovirus 71, and echovirus groups 6,9,11,14,19

Viral isolation from the throat, rectum, or other sites
Suckling mouse inoculation may be required to isolate the virus
Sera for Ab testing during the acute and convolescent periods showing an increased titer for an isolated virus suggests causality
PCR may be available in research labs

Supportive care
Treat secondary bacterial infections
IVIG has been used in severe infections
Pleconaril - investigational antiviral drug

Prognosis

Mortality up to 31% (71% if myocarditis present)
Most survivors do not have ongoing liver disease

Hepatotropic Viruses

Hepatictropic Viruses cause hepatitis as their primary infection but are an uncommon cause of neonatal and congenital hepatitis

Hepatitis A Virus (HAV)

Hepatitis B Virus (HBV)

Hepatitis C Virus (HCV)

Hepatitis D Virus (HDV)

Hepatitis E Virus (HEV)

Parvovirus B19, 5th Disease, Erythema infectiosum

Most known for "Slapped cheek" appearance, mild systemic symptoms, and fever
Can cause acute hepatitis, fulminant hepatitis with an assoc aplastic anemia and fetal hydrops
Dx:

Serology detection of IgM and IgG in blood
Viral DNA via PCR in blood or tissue samples

Monoclonal anti-CD52 Ab successful in a few cases
Consider IVIG in immunocompromised patients

Human Immunodeficiency Virus (HIV)

The majority of cases are due to vertical transmission from an infected mother
Other virus can co-infect the neonate more efficienctly when mother is co-infected with HIV
Clinical Manifestations:

Generalized lymphadenopathy, hepatomegaly, splenomegaly, failure to thrive, oral candidiasis, recurrent Diarrhea, parotitis, cardiomyopathy, hepatitis, nephropathy, central nervous system disease, lymphoid interstitial pneumonia, recurrent invasive bacterial infections, opportunistic infections, and malignancies
Liver manifestations may be due to opportunistic co-infection

Histology

Lobular and portal changes with lymphocytic infiltration, piecemeal necrosis, hepatocellular and bile duct damage, sinusoidal cell hyperplasia, and endothelialitis

In patients under 18mo: HIV culture and detection of HIV gene sequences via PCR

Antiretroviral therapy

Human Herpesvirus 6 (HHV6), Roseola infantum, 6th Disease, exanthum subitum

Clinical manifestations include Fever for several days with rapid defervescence followed by maculopapular red rash lasting 1-2 days
Acute liver failure and chronic hepatitis as been reported
Congenital infection results from Chromosomal Integration of the virus
Histology: Giant Cell Transformation, nonspecific lobular hepatitis with necrosis
Confirm Dx with PCR

Reovirus 3 infection

Proposed as viral candidate for neonatal hepatitis and biliary atresia

Several studies suggested elevated reovirus type 3 Ab titers in infants with biliary atresia and neonatal hepatitis
A monkey infected with reovirus developed biliary atresia
Association has not been confirmed. Reovirus may be one cause of neonatal hepatitis and biliary atresia (not the only cause)

Paramyxovirus

Rare cause (10 patients) of syncytial giant cell hepatitis

Severe hepatitis
Progression to chronic cholestasis and decompensted cirrhosis within the 1st yr of life
Histology:

syncytial multinucleated giant cells replacing hepatocyte cords most prominently in the centrilobular region, as well as severe acute and chronic hepatitis with bridging necrosis of hepatocytes, ballooning, and dropout of hepatocytes, cholestasis, and small round cell inflammation within the lobule.
Giant cells seen here are larger and different from those typically seen in neonatal hepatitis

References

Suchy
Wylie
Walker
Nelsons