The term neonatal hepatitis originated in the 1950s when few causes of neonatal liver disease were identified, and pathologists recognized a characteristic histologic appearance of the neonatal liver in response to injury. The term has since been used to refer to virtually all forms of liver dysfunction in the neonate that present clinically as jaundice due to conjugated hyperbilirubinemia within the first 3 months of life, after structural or anatomic disorders of the biliary tree have been excluded. However, this term is misleading because it implies an infectious process involving the liver (such as the numerous forms of viral hepatitis), because hepatic inflammation may not be a predominant histologic feature, and because it is a pathologic appearance rather than a diagnosis. A term proposed to circumvent these imprecisions is neonatal hepatitis syndrome , which emphasizes the uniformity of the clinical phenotype caused by the conglomerate of infectious, genetic, toxic, and metabolic causative disease processes leading to impaired excretory function and bile secretion. Advances in diagnostic technology have enabled identification of a host of discrete entities including inherited conditions such as the progressive familial intrahepatic cholestatic (PFIC) syndromes, bile acid synthetic defects, and more recently, citrin deficiency. As a result, the designation of idiopathic neonatal hepatitis continues to be used for neonatal liver disease for which no specific etiologic factor can be ascertained, after a thorough workup using contemporary technology. As newer disease entities are characterized, these terms are likely to become less useful.
Neonates have immature hepatic excretory functions, giving rise to a period of physiologic cholestasis. Almost any insult to the neonatal liver thus results in further impairment of the excretory machinery, leading to clinically significant cholestasis and elevated conjugated hyperbilirubinemia. For this reason, neonatal cholestasis is often used to describe the spectrum of presentations of neonatal liver injury. For practical purposes, neonatal cholestasis is defined as a conjugated bilirubin fraction greater than 20% of the total serum bilirubin level or serum conjugated bilirubin greater than 2 mg/dL (>34 µmol/L).
This chapter initially presents a diagnostic approach to the neonate with cholestasis. We then describe the more common infectious, endocrinologic, chromosomal, immunologic, and toxic etiologies that present with neonatal cholestasis. Finally, general principles of management of the cholestatic neonate are considered. Anatomic abnormalities including extrahepatic biliary atresia and each of the discrete inherited and metabolic entities leading to the common phenotype of pathologic cholestasis in the neonate are considered in other chapters.
Approach to the Infant with Cholestasis
The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Cholestasis Guidelines recommends that all infants who are jaundiced at 2 weeks of age (or 3 weeks if breast-fed and with normal history and no pale stools or dark urine) be screened for cholestasis with measurement of fractionated serum bilirubin. Disorders associated with cholestasis in the neonate are diverse, although the clinical presentation is similar, reflecting the underlying decrease in bile flow common to all the disorders. Early recognition of cholestasis in the infant and prompt identification of the treatable disorders such as sepsis, endocrinopathies (including panhypopituitarism and congenital hypothyroidism), and specific metabolic disorders (such as galactosemia, tyrosinemia type I, and inborn errors of bile acid metabolism) allow initiation of appropriate treatment to prevent progression of liver damage and, if possible, reverse damage that has already occurred. Table 68-1 outlines the wide variety of known etiologies. The most common discrete etiologies encountered are biliary atresia, α1-antitrypsin deficiency, infection, and parenteral nutrition–associated cholestasis. Early recognition of diagnostic clues may assist in differential diagnosis. Awareness of the multiple clinical complications common to all disorders with prolonged cholestasis leading to early application of medical therapy will improve the ultimate outcome and quality of life for these patients.
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Differentiation of extrahepatic obstruction (particularly biliary atresia) from intrahepatic etiologies is necessary both to identify disorders amenable to surgical intervention and to avoid the adverse outcomes reported with inappropriate surgery. A stepwise and organized approach should be taken in the diagnostic evaluation of each cholestatic infant ( Box 68-1 ), optimally involving close collaboration with radiology, surgical, and pathology colleagues.
History and physical examination
Includes family history, observation of stools, growth parameters, dysmorphic features, signs of fat-soluble vitamin deficiency
Confirm cholestasis and determine severity of liver disease and complications
Fractionated serum bilirubin
ALT, AST, alkaline phosphatase, GGT
Prothrombin time/INR and serum albumin
Glucose
Fat-soluble vitamin levels: vitamins A, D, and E
Initiate investigation for conditions requiring prompt specific therapy
Complete blood count
Blood venous gas
Bacteriologic: culture urine, blood, ± CSF
Virologic: viral cultures/PCR–urine, stool, blood ± CSF
Serologic: HSV, CMV, HHV-6, hepatitis A, B, and C, enterovirus
Urine-reducing substances
Galactosemia screen, erythrocyte galactose-1-phosphate uridyl transferase
Cortisol, TSH, T 4
Chest radiograph
Serum iron, ferritin
Urine organic acids (including succinylacetone, succinyl acetoacetate)
Investigate for more common causes not already excluded
α1-Antitrypsin level and phenotype
Abdominal ultrasonography, including Doppler studies *
* Note: These imaging studies are best performed in a unit experienced with their use and interpretation in neonates. Ultrasonography may be one of the initial investigations as it may identify an anatomic cause for cholestasis, obviating the need for further extensive investigation.
Hepatobiliary scintigraphy with pharmacologic priming *
Sweat chloride analysis
Investigate for less common causes not already excluded
Serum bile acids
Serum ammonia
α-Fetoprotein
Urine and plasma amino acids
Cholesterol
Skull, long bone (peroxisomal disorders), and spine radiography (Alagille)
Ophthalmologic consultation–embryotoxon, retinal examination
Cardiologic assessment including echocardiography
Liver biopsy for histology, electron microscopy, immunohistochemistry, viral culture
Cholangiography: intraoperative, percutaneous, ERCP, MRCP
Other specific diagnostic tests if indicated
Paracentesis and analysis of ascitic fluid if present (infection, bile)
Endocrine stimulation testing, magnetic resonance imaging of brain
Karyotype
Very long-chain fatty acids
Plasma acylcarnitines
Isoelectric focusing of serum transferrin
ANA, anti-Ro, anti-La antibodies
Bone marrow examination
Specific enzyme analysis in leukocytes or tissue (skin fibroblasts, muscle, liver)
Genetic testing: cystic fibrosis, Alagille syndrome, PFIC disorders
ALT, Alanine aminotransferase; AST, alanine aminotransferase; CMV, cytomegalovirus; CSF, cerebrospinal fluid; ERCP, endoscopic retrograde cholangiopancreatography; GGT, γ-glutamyltranspeptidase; HHV-6, human herpesvirus-6; HSV, herpes simplex virus; INR, international normalized ratio; MRCP, magnetic resonance cholangiopancreatography; PCR, polymerase chain reaction; TSH, thyroid stimulating hormone.
Clinical Features
A number of clinical features may provide clues during evaluation of the infant with jaundice due to conjugated hyperbilirubinemia ( Box 68-2 ), and thorough history taking and physical examination are mandatory. Liver disease should be suspected in a jaundiced infant whose urine is dark in color rather than light yellow or colorless. A history of persistently pale stools suggests extrahepatic obstruction such as caused by biliary atresia; however, acholic stools are not specific to this entity. Vomiting, poor feeding, lethargy, or irritability may indicate the presence of a generalized infectious process such as sepsis, or a metabolic condition such as galactosemia. The mother’s antenatal history may be significant for infectious illness associated with congenital infection. She may have a history of cholestasis related to taking estrogen-based contraceptives, or of intrahepatic cholestasis of pregnancy. Both are associated with mutations of the genes encoding the bile salt export pump (BSEP) or canalicular phospholipid transporter multidrug resistance protein 3 (MDR3), which can be passed onto the infant resulting in progressive familial intrahepatic cholestasis (PFIC) types 2 and 3, respectively. A parental history of gallstones may be significant, as this has also been associated with MDR3 mutations. Fatty acid oxidation disorders in the fetus have been associated with the development of acute fatty liver of pregnancy (AFLP) and, to a lesser extent, with preeclampsia accompanied by the syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP). A maternal history of thrombophilia has been associated with a fetal thrombotic vasculopathy resulting in severe neonatal liver disease including Budd-Chiari syndrome. Maternal medication and drug history are also important, as amphetamine abuse, anticonvulsant drugs, and fetal alcohol syndrome can all present with neonatal cholestasis. The early neonatal history may be significant for asphyxia causing hypoxic liver injury, and similarly congenital heart disease, prematurity, or gastrointestinal complications that required treatment with parenteral nutrition. Neonatal exposure to medications such as fluconazole or micafungin may cause cholestasis, whereas third-generation cephalosporin use can result in biliary sludge. A temporal association of illness with ingestion of lactose- or fructose-containing feeds, or medications containing fructose, may suggest galactosemia or fructosemia, respectively.
Racial background
Amish: PFIC type 1, familial hypercholanemia
Greenland Eskimo: Nielsen syndrome (familial Greenland cholestasis)
North American Indian (Ojibway-Cree): North American Indian cirrhosis
East Asian: Citrin deficiency
Norwegian: Aagenaes syndrome (lymphedema cholestasis syndrome)
Family history
Lung or liver disease: α1-antitrypsin deficiency
Lung disease: cystic fibrosis
Congenital heart disease: Alagille syndrome
Maternal history of hepatobiliary problems
Intrahepatic cholestasis of pregnancy: PFIC types 2 and 3
Preeclampsia with HELLP: fatty acid oxidation disorders
Other maternal history
SLE or Sjögren disease: neonatal lupus erythematosus
Dysmorphism
Alagille syndrome
Trisomies
Micropenis–hypopituitarism
Cleft palate–Kabuki syndrome, Hardikar syndrome
Chubby cheeks–citrin deficiency
Neurologic abnormalities
Niemann-Pick type C
Septo-optic dysplasia (hypopituitarism)
Congenital disorders of glycosylation
Early onset severe liver dysfunction (synthetic dysfunction)
Herpes simplex virus
Neonatal iron storage disease or gestational alloimmune liver disease
Tyrosinemia type I
Galactosemia
Niemann-Pick C
Hemophagocytic lymphohistiocytosis
Mitochondrial respiratory chain dysfunction
Bile acid synthetic disorders
Temporal association with dietary commencement/changes
Galactosemia
Fructosemia
Cholestasis/pruritus but anicteric
PFIC type 2
Bile acid synthetic disorders
Familial hypercholanemia
Low or normal serum GGT
PFIC type 1 or 2
Bile acid synthetic disorders
Endocrine causes
Arthrogryposis–renal tubular dysfunction–cholestasis syndrome
Lymphedema cholestasis syndrome (Aagenaes syndrome)
Renal disease
Tyrosinemia type I
Ductal plate malformation/fibrocystic diseases: congenital hepatic fibrosis, ARPKD
Alagille syndrome
Arthrogryposis–renal tubular dysfunction–cholestasis syndrome
ARPKD, Autosomal recessive polycystic kidney disease; GGT, γ-glutamyl transpeptidase; HELLP, hemolysis, elevation of liver enzymes and low platelets; PFIC, progressive familial intrahepatic cholestasis; SLE, systemic lupus erythematosus.
It is important to review serial infant growth parameters. Small-for-gestational-age at birth and failure to thrive occur with congenital infection and chromosomal abnormalities. Gestational alloimmune liver disease (GALD; formerly known as neonatal iron storage disease) often begins in utero , and intrauterine growth restriction is associated. In contrast, infants with biliary atresia tend to have normal growth parameters at diagnosis. A number of characteristic dysmorphic syndromes are associated with neonatal cholestasis, including trisomy 21, trisomy 18, Zellweger, Smith-Lemli-Opitz, and Alagille syndromes. Infants with citrin deficiency have a characteristic facial appearance with “chubby cheeks.” A cleft palate and a history of gastrointestinal or genitourinary obstruction suggest Hardikar syndrome. Abdominal examination may reveal a palpable mass in the case of tumor or choledochal cyst. Splenomegaly suggests early cirrhosis with portal hypertension, congenital infection, Niemann-Pick type C, or other lysosomal storage disease such as Gaucher disease type 2, which can present as cholestasis. Examination of the genitalia may reveal a micropenis or cryptorchidism, suggestive of panhypopituitarism. The skin should be examined for complications of cholestasis such as bruising, although xanthomatosis and scratch marks typically are not observed in the neonate. Ichthyosis may suggest neonatal ichthyosis sclerosing cholangitis (NISCH) syndrome, or be a clue to the arthrogryposis-renal-cholestasis (ARC) syndrome, which may present without arthrogryposis. Purpuric rashes occur with congenital infections such as cytomegalovirus (CMV), toxoplasmosis, and rubella. Infiltrative skin lesions occur with juvenile xanthogranuloma and Langerhans cell histiocytosis. The café-au-lait skin macules of McCune-Albright syndrome usually manifest beyond the neonatal period. Abnormalities of the cardiovascular system such as peripheral pulmonary stenosis are associated with Alagille syndrome and dextrocardia/situs inversus with the “embryonic” form of biliary atresia. Cardiologic assessment including echocardiography can be helpful in detecting subtle anomalies. Neurologic abnormalities such as hypotonia, hyporeflexia, and ataxia may be caused by vitamin E deficiency secondary to cholestasis, or associated with specific disease entities such as Niemann-Pick type C and peroxisomal and mitochondrial respiratory chain disorders. Signs of rickets such as rib rosary, flared metaphyses, or craniotabes suggest severe vitamin D deficiency secondary to cholestasis. Ophthalmologic examination may be helpful in revealing the persistent posterior embryotoxon of Alagille syndrome, retinal changes with septo-optic dysplasia (these infants may also display nystagmus), or cataracts with galactosemia or peroxisomal disorders.
Laboratory and Radiographic Evaluation
The goal of the optimal investigative approach to the cholestatic infant is to evaluate the severity of liver disease, assess for the presence of complications of chronic cholestasis, and provide a timely final diagnosis while minimizing risk to the infant in a cost-effective manner. Box 68-1 outlines a staged approach that excludes treatable life-threatening conditions early, and then considers investigations relevant for more common conditions, and finally those investigations that are either more specialized or targeted at specific conditions. In clinical practice, investigations are initiated simultaneously, with clinical features and results of preliminary investigations steering further evaluation. The precise point of involvement of subspecialty support will vary according to the case and local resources.
Standard liver biochemical tests include serum total and conjugated (direct) bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyl transpeptidase (GGT). Delta bilirubin (conjugated bilirubin bound to albumin) could be used to assess long-term cholestasis; however, it remains elevated even when hepatic injury is resolved. Elevated aminotransferase concentrations typically indicate primarily hepatocellular damage, whereas elevations of ALP and GGT indicate biliary tract injury or obstruction. Serum GGT is elevated in most cholestatic disorders including biliary atresia, Alagille syndrome, and α1-antitrypsin deficiency. GGT level can also be elevated in parenteral nutrition–related cholestasis. A low or normal GGT level in the presence of a conjugated hyperbilirubinemia merits further workup for rarer entities such as PFIC types 1 or 2 or primary bile acid synthetic defects, although it may also be seen with endocrinologic causes for cholestasis (see Box 68-2 ). Serum glucose, albumin, and a coagulation profile provide an indication of the synthetic functional capacity of the liver and allow intervention for the serious complications of hypoglycemia and coagulopathy, if present. Abnormal coagulation indices out of proportion to what would be expected for the degree of conjugated hyperbilirubinemia can be seen with severe vitamin K deficiency or may be an early indication of metabolic liver disease such as tyrosinemia type I or GALD. Chronic cholestasis results in fat-soluble vitamin deficiency and measurement of vitamin A, D, and E levels and prothrombin time/international normalized ratio (INR) are useful in screening for these complications.
Because bacterial sepsis, severe viral infections, hypopituitarism, and metabolic conditions such as galactosemia and tyrosinemia type I can cause rapid deterioration and even death without prompt recognition and treatment, it is important that these conditions be among those excluded early in the diagnostic process. Thus, appropriate bacterial and viral cultures, serology, and molecular testing are important to consider early. Urine-reducing substances can be tested at the bedside, and if positive can suggest galactosemia, but they may be falsely negative in a patient with galactosemia either not receiving lactose (e.g., fasting, on parenteral nutrition, or receiving a lactose-free formula) or vomiting excessively before assessment. Measurement of red blood cell galactose-1-phosphate uridyl transferase activity (with the proviso that the infant has not received a recent blood transfusion) is useful in this situation. Endocrinologic causes can be screened by measurement of thyroid-stimulating hormone, free thyroxine (T 4 ), and cortisol levels. A chest radiograph is useful in the sepsis workup, but also may provide other diagnostic clues such as dextrocardia associated with the embryonal form of biliary atresia, or the butterfly vertebrae of Alagille syndrome. Grossly elevated ferritin levels, typically greater than 1000 µg/L, but can exceed 100,000 µg/L, are seen with GALD. Increased urinary succinylacetone is pathognomonic for tyrosinemia type I.
Biliary atresia, although not immediately life threatening, is a common cause of neonatal cholestasis, with improved outcomes if treated early with Kasai portoenterostomy. A combination of imaging and pathology assists with this diagnosis (see later discussion). α1-Antitrypsin phenotype by isoelectric focusing is important, because serum α1-antitrypsin levels may be normal in infants with liver disease due to α1-antitrypsin deficiency. α-Fetoprotein (AFP) levels are normally high at birth and decline rapidly over subsequent weeks. Excessively high levels in the setting of cholestasis are seen with malignancy such as hepatoblastoma and citrin deficiency. Sweat chloride testing may identify infants with cystic fibrosis and should be considered early in known patient populations with a high prevalence of this condition. Low or undetectable serum bile acid levels in the setting of other signs or symptoms of cholestasis suggest bile acid synthetic disorders. Hyperammonemia may be present with citrin deficiency, or in the setting of severe liver failure. Patterns of elevated plasma amino acids can help distinguish citrin deficiency from other urea cycle disorders. Low serum cholesterol, especially in the cholestatic infant with dysmorphism or neurologic abnormalities, suggests a peroxisomal disorder. It can be significantly elevated in Alagille syndrome, but is nonspecific.
Among the available imaging modalities, ultrasonography is noninvasive and provides information about liver structure, size, composition, and vascular flow, and therefore it is best used as an initial imaging modality. Ultrasonography can delineate external biliary anatomy and identify signs of obstruction such as duct dilation, abnormalities of the ducts themselves such as caused by a choledochal cyst or Caroli’s disease, and extrinsic masses or tumors causing biliary compression. A number of signs are associated with biliary atresia, including sonographic absence of the gallbladder, lack of visualization of extrahepatic ducts, and the “triangular cord sign.” This latter sign reflects a fibrous cone of tissue at the porta hepatis and has been reported to have positive predictive values between 78% and 95% for biliary atresia. High frequency ultrasonography (higher than 30 MHz, compared to conventional ultrasonography that typically uses 2 to 15 MHz) is a promising new method for improving imaging of the biliary tract; a recent study reported a sensitivity of 91.3%, specificity 92.9%, and accuracy of 92.2% in diagnosing biliary atresia. It is proposed that combining the triangular cord sign with gallbladder measurements can improve ultrasonographic accuracy in diagnosing biliary atresia; however, because given operator dependency of ultrasonography, experience and care in the performance of the scan, and interpretation of the images are required. Ultrasonography can also detect gallstones and biliary sludge, as well as demonstrate complications of liver disease such as splenomegaly, ascites, or the development of intraabdominal collateral vessels reflecting portal hypertension. Hepatobiliary scintigraphy using technetium-99m iminodiacetic acid derivatives has been used to differentiate nonobstructive causes of neonatal cholestasis from extrahepatic biliary atresia. Hepatic uptake and secretion into bile of intravenously administered iminodiacetic acid derivatives occur by carrier-mediated organic anion pathway and depend on the structure of the specific analog, the integrity of hepatocellular function, and biliary tract patency. Pretreatment with oral phenobarbital (5 mg/kg per day for 3 to 5 days) or ursodeoxycholic acid (20 mg/kg twice daily for 2 to 3 days) stimulates bile secretion and enhances the ability to detect biliary excretion of the isotope into the intestinal tract. When time is constrained and investigation with hepatobiliary scintigraphy is deemed necessary as per institution-specific protocols, proceeding without a pretreatment agent is possible, since positive identification of radioactivity in the intestine confirms patency of the biliary tree. One study using planar imaging found sensitivity of 100% and specificity of only 74% for diagnosing biliary atresia. A study using single-photon emission computed tomography (SPECT) found that in combination with phenobarbitone stimulation, a sensitivity of 100% and specificity of 97% for biliary atresia could be achieved.
Liver biopsy remains an important tool for evaluating neonatal cholestasis. Tissue may be obtained via percutaneous needle biopsy, or as a wedge biopsy at the time of a laparoscopy/laparotomy performed for cholangiography or portoenterostomy procedure. Bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis best predicted biliary atresia on liver histology. Cytokeratin immunohistochemistry is a useful tool to highlight biliary structures in liver tissue and aid the morphological assessment. The histologic findings of nonobstructive causes of neonatal cholestasis are variable and often nonspecific. Giant cell transformation is a common response of the neonatal liver to any of a number of heterogeneous insults and occurs predominantly around central veins ( Figure 68-1 ). Paucity of intralobular bile ducts may indicate Alagille syndrome, though in premature infants and term neonates within the first month of life, interlobular ducts are still forming, and so experience in interpreting these biopsies is essential. The histologic assessment of the biopsy is enhanced with specialized processing techniques, stains, and immunohistochemistry, which assist in the diagnosis of conditions such as α1-antitrypsin deficiency and viral infections such as CMV. Electron microscopy may provide additional information such as the granular appearance of “Byler’s bile” in PFIC type 1, or the presence of viral particles. Liver tissue may also be diagnostic when subjected to enzymatic testing such as with mitochondrial respiratory chain disorders.
Direct demonstration of the extrahepatic biliary passages via operative cholangiography is indicated when liver histopathology suggests extrahepatic bile duct obstruction and the results of hepatobiliary scintigraphy are consistent with such an interpretation. Traditionally this has been with direct cholangiography via percutaneous transhepatic cholangiography or cholecystocholangiography, or via operative cholangiography. Other less invasive options now utilized include laparoscopic cholangiography, endoscopic retrograde cholangiography, and magnetic resonance cholangiopancreatography. The optimal cholangiographic study will depend on other differential diagnoses and institutional expertise, emphasizing the need for close collaboration among the physician, surgeon, and radiologist.
Investigations that are more specialized are generally reserved for situations in which clinical features or previous tests suggest a rare diagnosis, or when preceding investigations have not yielded a diagnosis. Endocrine stimulation testing or pituitary MRI can confirm a diagnosis of hypopituitarism. Genetic studies include a karyotype to demonstrate trisomy 18 or 21, and specific gene testing, where available, for conditions such as Alagille syndrome, the PFIC, and cystic fibrosis. Plasma acylcarnitine analysis can identify specific disorders of fatty acid oxidation. Very long-chain fatty acids are elevated with peroxisomal disorders. Isoelectric focusing of transferrin can diagnose most congenital disorders of glycosylation. On bone marrow examination, macrophages may have a “crinkled tissue paper” appearance with Gaucher disease or a foamy appearance with Niemann-Pick type C or Farber disease. Activity of specific enzymes can be tested on leukocytes, cultured fibroblasts, or tissue when confirming diagnoses of peroxisomal disorders, Niemann-Pick type C, glycogen storage disease type IV, or mitochondrial respiratory chain disorders.
Cholestasis Associated with Infection
Various bacterial, viral, and protozoal agents are associated with neonatal cholestasis, resulting from pre-, peri-, or postnatal infections.
Bacterial Infections
Extrahepatic bacterial infection, either generalized or localized, has long been recognized as a cause of conjugated hyperbilirubinemia in infants. The mechanisms by which this occurs are being elucidated with increasing knowledge of the molecular mechanisms of bile acid processing and transport within the hepatocyte and their regulation by nucleic factors. Bacterial endotoxin and inflammatory cytokines released by activated Kupffer cells have been shown to reduce both basolateral and canalicular transport of bile acids. These effects are mediated by alterations in the expression and function of hepatocyte nuclear receptors. The transporters responsible for hepatocyte uptake of unconjugated bilirubin and excretion of conjugated bilirubin are also affected, although the conjugating machinery is not. The relatively immature bile acid transport mechanisms of newborns may make this group susceptible to developing clinically evident cholestasis during episodes of sepsis, although it is important to remember that the infant need not appear clinically very ill for this to occur. The most common site for infection in these infants is the urinary tract, and Escherichia coli is the most common organism involved, although other sites and organisms have been reported. Galactosemia is associated with increased risk of gram-negative sepsis and thus should be excluded in infants with liver disease and these infections.
Bacterial cultures of blood and urine obtained in a sterile fashion are an important part of the workup of neonatal cholestasis. Cerebrospinal fluid cultures should also be considered. This should be followed by the immediate initiation of appropriate empiric antibiotic therapy in an infant suspected to have sepsis.
Congenital Syphilis
Congenital syphilis is caused by Treponema pallidum , contracted from an infected mother via transplacental transmission at any time during pregnancy or at delivery by contact with maternal secretions. At the time of infection, T. pallidum is liberated directly into the circulation of the fetus (spirochetemia). The clinical, laboratory, and radiographic abnormalities of congenital syphilis are a consequence of the inflammatory response to spirochetes induced in various body organs and tissues. The signs and symptoms of congenital syphilis are divided arbitrarily into early manifestations and late manifestations. Clinical features in the neonatal period may include a snuffly nose; hepatosplenomegaly; lymphadenopathy; mucosal lesions; painful bone and cartilage lesions; an erythematous, scaly maculopapular rash; and chorioretinitis. Thrombocytopenia and hemolytic anemia may also be present. Late manifestations tend to occur after age 2 years and include destructive bone lesions, a “saddle-nose” deformity, and Hutchinson teeth. Diagnosis involves confirming infection in the mother (if not already done) and comparing infant nontreponemal (venereal disease research laboratory [VDRL], rapid plasmin reagin [RPR]) titers with those of the mother. Evaluation of the infant also includes a complete blood count (including platelet count), cerebrospinal fluid for cells, protein, and VDRL titer. If clinically indicated, radiography of the chest and long bones, neuroimaging, auditory brainstem responses, eye examination, and liver function tests are also recommended.
Neonatal liver disease has been associated with congenital syphilis. Jaundice may occur within the first day of life and mimic erythroblastosis fetalis, or present as later-onset jaundice. Hepatomegaly is the most common clinical sign in congenital syphilis, and results mainly from extramedullary hematopoiesis. A more fulminant presentation with subsequent hepatic calcification also has been reported, as has hypopituitarism as a complication of congenital syphilis.
Liver biopsy is not necessary if a clear diagnosis of congenital syphilis is made. Histologic evaluation may show a characteristic centrilobular mononuclear infiltrate with extensive fibrosis of the interstitia and of the portal triads surrounding the bile ducts and blood vessels, and giant cell transformation. Bile duct paucity has been reported. Silver stains or transmission electron microscopy may reveal spirochetes, most commonly in the space of Disse and between reactive mesenchymal cells. Gumma lesions, characterized by a central zone of necrosis surrounded by a dense infiltrate of lymphocytes, plasma cells, histiocytes, epithelioid cells, and giant cells, are seldom seen in early congenital syphilis.
Treatment with 10 days of parenteral penicillin is recommended. For penicillin allergy, desensitization is preferred over use of alternative antibiotics. Liver disease may be exacerbated by penicillin therapy before improving. The liver disease often resolves slowly, even after apparently adequate therapy. There are no known long-term liver sequelae for infants adequately treated for congenital syphilis.
Perinatal Tuberculosis
Neonatal liver infection with Mycobacterium tuberculosis is very rare. Perinatal tuberculosis can be acquired by the infant (1) in utero by transplacental hematogenous spread via the umbilical vein from the infected mother, or by ingestion of infected amniotic fluid; (2) intrapartum by ingestion or inhalation of infected amniotic or maternal fluids, or by direct contact with maternal genital tract lesions; or (3) postnatally by ingestion or inhalation of material from an infectious source (which may not be the mother). Maternal history may not be helpful, because most pregnant women with tuberculosis are asymptomatic.
Neonates typically present after 2 weeks of age with fever, hepatomegaly, and respiratory symptoms, and are often initially treated for presumed bacterial sepsis. Presentation with progressive liver dysfunction without pulmonary symptoms, or as part of a multiorgan dysfunction, may also occur. Liver histopathology is not necessary for diagnosis, but shows granulomatous hepatic lesions with or without caseation, surrounding giant cells and lymphocytes, and epithelioid cells with tubercle bacilli. Diagnostic testing includes the tuberculin skin test, chest radiograph, lumbar puncture, obtaining appropriate fluid or tissue for acid-fast bacilli staining, mycobacterial cultures, and/or polymerase chain reaction (PCR) testing. Specimens include cerebrospinal fluid, gastric fluid aspirates, ascitic fluid, tracheal aspirates, and lymph node or bone marrow biopsies. Because of the relative immaturity of their immune systems, the skin test result very rarely is positive in infants and may indeed be negative in the mother because of anergy associated with pregnancy. Therefore, examination for tubercle bacilli and mycobacterial cultures of appropriate body fluid specimens is essential. At present, there is insufficient experience with interferon γ release assays in the diagnosis of perinatal tuberculosis. Treatment of suspected perinatal tuberculosis should not be delayed pending the results of mycobacterial cultures and involves prompt commencement of isoniazid, rifampin, pyrazinamide, and an aminoglycoside such as amikacin. Corticosteroids are added if tuberculous meningitis is also present. The prognosis is poor with disseminated extrapulmonary disease and with coexistent human immunodeficiency virus (HIV) infection, although successful treatment of perinatal tuberculosis involving the liver has been reported.
Listeriosis
Listeria monocytogenes infection in the neonatal period causes severe illness and may have an early (within the first days of life) or late (after 1 week of age) onset. Transmission of this gram-positive bacillus occurs via the transplacental route or at delivery from infected cervicovaginal secretions. In utero infections typically result in premature delivery. In contrast to the infant, maternal illness in typically mild, and may include fever, flulike symptoms, or diarrhea. Early infection is usually disseminated and characterized by multiple organ involvement. Meningitis occurs with the late-onset form. Hepatic manifestations are always present in these critically ill infants. Hepatosplenomegaly occurs with or without jaundice. Liver histopathology shows diffuse hepatitis or miliary microabscesses containing abundant gram-positive rods. A severe early form of the infection may be accompanied by an erythematous rash with pale papules that are granulomatous histologically. Diagnosis is made by isolating the organisms from blood, meconium, cerebrospinal fluid, or the liver. Treatment is with ampicillin and an aminoglycoside such as gentamicin, although mortality remains as high as 30% to 50% despite therapy.
Viral Infections
Cytomegalovirus
Cytomegalovirus (CMV) is a member of the Herpesviridae family and is a common congenital infection, with approximately 1% to 2% of all live-born infants infected in utero and excreting the virus at birth. Transmission occurs in utero by transplacental passage of maternal bloodborne virus, at delivery by passage through an infected maternal genital tract, postnatally via maternal breast milk or saliva, or iatrogenically from transfusion of blood products.
For the 90% of neonates with congenital CMV infection that are asymptomatic, infection may not be detected, although up to 7.2% of these infants will later develop sensorineural hearing loss. Typical clinical features in those with overt disease in the neonatal period include hepatomegaly, splenomegaly, jaundice, petechiae, or purpura secondary to thrombocytopenia, pneumonia, microcephaly, chorioretinitis, and neurologic features such as poor feeding, hypotonia, or seizures due to cerebral calcifications. Hepatosplenomegaly is caused by mild hepatitis, a reticuloendothelial response to chronic infection, and extramedullary hematopoiesis. CMV hepatitis is usually associated with a conjugated hyperbilirubinemia and mild elevation of liver transaminases, and hepatomegaly may persist for up to a year. Although CMV hepatitis is usually mild, the following complications have been reported: ascites, bleeding diathesis, disseminated intravascular coagulopathy, secondary bacterial infections, and ensuing death. Hepatic histopathology includes multinucleated giant cell transformation, large inclusion-bearing cells, cholestasis, cholangitis, and extramedullary hematopoiesis. The characteristic finding is an enlarged (endothelial, hepatocyte, or bile duct epithelial) cell containing basophilic granules in the cytoplasm and a swollen nucleus. An amphiphilic intranuclear inclusion is surrounded by a clear halo, resembling an owl’s eye ( Figure 68-2 ). Both nuclear and cytoplasmic inclusions represent closely packed virions. Liver calcifications may also be found on imaging.
CMV infection should be excluded in all neonates with prolonged cholestasis. Isolation of the virus from tissue cultures or detection in urine, saliva, blood, cerebrospinal fluid, and tissue biopsies by culture or PCR all can be used to diagnose CMV infection. Assessment of extrahepatic involvement should be part of the routine workup including funduscopy, brain ultrasound, and computed tomographic (CT) scan and assessment of hearing by brainstem-evoked potentials.
There is a benefit of intravenous ganciclovir treatment for infants with congenital CMV infection who are manifesting neurologic symptoms, in terms of reduced rates of hearing loss and possibly other developmental outcomes. The toxicity of this treatment, which is given for 6 weeks, included neutropenia in almost two-thirds of patients. Recent publications reported that oral valganciclovir, dosed at 15 mg/kg twice per day for 6 weeks, could be used as an alternative therapy for CMV infection in symptomatic infants, with 67% (8 of 12) newborns reported to have negative CMV DNA in urine and plasma at the end of the 6-week study period. Nonetheless, one of the pitfalls of these studies was the small number of patients included (N = 13). Although hepatomegaly and mild alteration in liver function test results may persist for several months after birth, severe chronic liver disease rarely occurs, and there is no evidence to support treatment unless neurologic features are present.
Herpes Simplex Virus
Neonatal herpes simplex virus (HSV) infection can manifest as a disseminated disease involving multiple organs, most prominently liver and lungs; localized central nervous system (CNS) disease; or disease localized to the skin, eyes, and mouth. Overall, HSV type 2 strains cause more infections in neonates than HSV type 1 strains; however, HSV-1 was more common in a case series of patients with neonatal liver failure. In the United States, the incidence of neonatal HSV infection is estimated to be 1:3200 live births. Prematurity is a risk factor, with premature infants accounting for 40% to 50% of cases of neonatal herpes and having a greater likelihood of having a fatal outcome. Whether the increased frequency of prematurity among neonates with herpes indicates a greater propensity of mothers with genital herpes to deliver prematurely or a greater susceptibility of premature infants to HSV infection remains unknown. Transmission occurs during delivery via exposure to an infected maternal genital tract, by ascending infection, or postnatally from a parent or other caregiver (most often from a nongenital infection such as the mouth or hands). It is important to note that in most cases of neonatal HSV infection, the mother has no history or current evidence of herpetic genital lesions.
HSV hepatitis presents as part of a generalized herpetic disease in the newborn infant, including a fulminant presentation with jaundice, hepatomegaly, conjugated hyperbilirubinemia and elevated transaminases, major abnormalities of blood clotting factors, and bleeding complications. At least 20% will not display the typical vesicular rash of cutaneous involvement. Liver histopathology reveals generalized or multifocal hepatocyte necrosis and cholestasis with characteristic intranuclear acidophilic inclusion bodies representing the herpes simplex virions.
Diagnosis of neonatal HSV infection is confirmed by viral culture of specimens from the skin (such as scrapings of the base of skin lesions if present), conjunctivae, oropharyngeal mucosa, stool, urine, and CSF. Rapid diagnosis can be achieved using detection of viral DNA by PCR, or from skin lesions by direct immunofluorescence or enzyme immunoassay. PCR testing of CSF and blood is positive in more than 90% of infants with disseminated disease, although lumbar puncture is not recommended in the setting of coagulopathy. Serology testing is of little value because of possible confounding by the presence of maternal immunoglobulin G (IgG) in the infant’s serum. Liver biopsy is not usually necessary for diagnosis and indeed would be risky, given the coagulopathy that is often present in these infants.
Three weeks of treatment with parenteral acyclovir reduces mortality to 29% in disseminated disease, as compared to historical data in which mortality was 85% with no antiviral treatment. Poor prognostic factors included lack of skin lesions, degree of thrombocytopenia and coagulopathy, and severe cholestasis and detection of HSV DNA by PCR. Successful liver transplantation has been reported in patients presenting in neonatal acute liver failure secondary to HSV.
Congenital Rubella
Rubella virus is an enveloped RNA virus in the family Togaviridae. Although rubella usually is a mild, often subclinical disease affecting school-age children and young adults, congenital rubella syndrome is associated with multiple anomalies. These congenital malformations include ophthalmologic (cataracts, retinopathy, and congenital glaucoma), cardiac (patent ductus arteriosus and peripheral pulmonary artery stenosis), auditory (sensorineural hearing impairment), and neurologic (behavioral disorders, meningoencephalitis, and mental retardation). Additional features include growth retardation, radiolucent bone disease, hepatosplenomegaly, thrombocytopenia causing a purpuric rash, and the “blueberry muffin” lesions of hematopoiesis within the skin.
Hepatic manifestations range from jaundice, hepatosplenomegaly, and transient cholestasis to a late anicteric hepatitis. Hepatosplenomegaly persists for longer periods and resolves after 12 months or longer. Diagnosis of congenital rubella is made by the detection of rubella-specific IgM antibody in serum or oral fluid, viral isolation, or detection of viral RNA by PCR in nasopharyngeal swabs, blood, or body fluid. Liver histology typically demonstrates giant cell hepatitis. Infants with congenital rubella usually recover from the hepatitis, and most of their morbidity relates to structural heart disease and neurologic complications. Treatment for congenital rubella is supportive. Immunization of prepubertal girls offers the best hope for prevention of this disease.
Enteroviruses
The nonpolio enteroviruses are single-stranded RNA viruses belonging to the family Picornaviridae and include coxsackievirus A and B, echoviruses, and the “numbered” enteroviruses. Neonatal infection with coxsackieviruses and echoviruses can result from transplacental viral transmission, contact with infected secretions during birth, and human-to-human contact after birth. Coxsackieviral and echoviral infections in neonates result in a wide variety of clinical manifestations, ranging from asymptomatic infection to fatal hepatitis, encephalitis, myocarditis, and disseminated intravascular coagulation. The most common manifestations are nonspecific, including fever, irritability, and lethargy, which lead to an evaluation for bacterial sepsis. Some infants display a maculopapular rash. Although enteroviral infections tend to occur most commonly in the winter and fall, there appears to be less seasonality in neonatal presentations. There is often a history of recent maternal or other close contact illness.
The viruses associated with severe hepatitis, often with hepatic necrosis, include echovirus 6, enterovirus 71, and coxsackieviruses B1–4. Liver calcifications may develop in survivors of coxsackievirus B1 hepatitis.
Specimens providing the highest yield for virus culture are swabs or fluids obtained from the respiratory or gastrointestinal tract or from CSF. Diagnosis can also be made by detecting enteroviral RNA using reverse-transcriptase PCR. Serology testing is of limited value because of low sensitivity resulting from a lack of a common antigen in so many antigenically different enteroviruses.
Treatment is primarily supportive. Pleconaril is a promising antiviral agent with demonstrable benefit in the treatment of immunodeficient children and infants with severe enterovirus infections. A multicenter randomized double-blinded placebo-controlled trial in infants younger than 12 months with suspected enterovirus meningitis failed to prove efficacy; however, this could have been related to the small number of patients and benign clinical course of the disease. Intravenous immunoglobulin (IVIg) has been used for both postexposure prophylaxis and treatment, but no strong evidence for efficacy exists. In those neonates with severe hepatitis, mortality has been reported as 24% to 31% in larger series, and up to 71% if myocarditis is also evident. Most survivors do not have residual hepatic impairment.
Hepatotropic Viruses
The hepatotropic viruses, hepatitis A virus (HAV), B (HBV), C (HCV), D (HDV), and E (HEV), cause hepatitis as their primary disease manifestation, but likely play a limited role in clinical neonatal disease. In infants, HAV and HBV infections are generally asymptomatic. Neonatal cholestasis resulting from vertical transmission of HAV infection has been reported. HBV is vertically transmitted during pregnancy or delivery. Depending on the mother’s e-antigen status, the risks of transmission can be reduced from up to 90% down to 1% to 10% with active and passive immunization of the newborn. Most infected infants will become asymptomatic carriers, although rarely a fulminant hepatitis may occur. HCV can be transmitted perinatally, with some infected infants having mild-to-moderate elevation of aminotransferase levels, and death from liver failure has been reported. Perinatal transmission of HDV is uncommon and occurs in the presence of HBV transmission. Vertical transmission of HEV may be common and has been reported as causing a high rate of icteric hepatitis, which may be fatal. Hence, screening for the hepatotropic viruses in infants presenting with prolonged cholestasis remains in diagnostic algorithms. Chapter 75 provides further discussion of these viruses in older children and adolescents.
Human Immunodeficiency Virus
HIV infection in children causes a broad spectrum of disease and a varied clinical course. Acquired immunodeficiency syndrome (AIDS) represents the most severe end of the clinical spectrum. The established modes of HIV transmission include sexual contact; percutaneous or mucous membrane exposure to contaminated blood or other body fluids with high titers of HIV; mother-to-infant transmission before or around the time of birth; and breast-feeding. Children with HIV infection often develop liver disease, which may be as a result of cytopathic effects of the virus, opportunistic infections, or hepatotoxicity related to medications, or through metabolic derangements such as nonalcoholic fatty liver disease. Clinical manifestations include failure to thrive, recurrent diarrhea, oral candidiasis, hepatitis, hepatomegaly, and splenomegaly, as well as generalized lymphadenopathy, parotitis, cardiomyopathy, nephropathy, central nervous system disease (including developmental delay), lymphoid interstitial pneumonia, recurrent invasive bacterial infections, opportunistic infections, and specific malignant neoplasms. Cholestatic hepatitis may be the first manifestation of HIV infection in young infants and has caused fatal liver failure. Giant cell hepatitis has been reported in relation to vertically acquired HIV infection. Antiretroviral agents used to prevent vertical transmission may also cause cholestasis in the neonate. Vaccination against HIV is promising and clinical trials are on the way.
Other Viruses
Human herpes virus (HHV)-6, the cause of childhood roseola infantum with fever and exanthem subitum, has been associated with cholestasis, neonatal hepatitis, giant cell transformation, and fatal fulminant hepatitis. There may be accompanying thrombocytopenia. It has recently been shown that congenital infection results from chromosomal integration of the virus. The histopathology is of a nonspecific lobular hepatitis with necrosis. Giant cell hepatitis has been described as a histologic feature of HHV-6 infection. Diagnosis is confirmed by serology, which may be negative in the acute phase, or PCR on body fluids and infected tissues.
Human parvovirus (B19 virus), the cause of erythema infectiosum in childhood, is thought to principally infect pronormoblastic erythroid cells, resulting in severe hemolytic anemia in the fetus with hydrops. Many fetal organs, including the liver, are affected, and hepatocyte necrosis has been reported in fetuses and in newborn infants with parvovirus infection. An acute severe hepatitis has been described in an older infant in association with parvovirus B19 infection. Diagnosis of parvovirus B19 is confirmed by serology with detection of IgM and IgG in blood samples or by the detection of virus by PCR in blood or tissue samples.
Adenoviruses are DNA viruses that most commonly infect the upper respiratory tract. Transmission is either perinatal during delivery or postnatal through contact with infected caregivers. Life-threatening disseminated infection occasionally occurs among young infants and immunocompromised hosts, with severe hepatitis and liver failure. The pathology is similar to that seen in HSV infection, with widespread hepatocyte necrosis and intranuclear viral inclusion bodies. Diagnosis is confirmed by isolation of the virus from nasopharyngeal or pulmonary secretions or by detection of viral DNA by PCR in infected tissues, such as the liver and lungs.
Maternal varicella infection in the last 3 weeks of pregnancy can result in neonatal varicella infection, which generally occurs within the first 10 to 12 days of life. Illness is more severe if maternal infection manifests between 5 days before and 2 days after delivery. Severe necrotizing hepatitis may occur as a feature of multisystem involvement that may include extensive skin lesions, pneumonitis, and meningoencephalitis. Varicella acquired postnatally can also present with a severe hepatitis and has been associated with hemolytic anemia. It has been described that varicella acquired prenatally, however, can present with severe visceral complications. Treatment is with acyclovir, and zoster immunoglobulin is used to prevent severe disease in newborns whose mothers manifest infection late in pregnancy or shortly after delivery.
Transfusion-transmitted virus (TTV) is an unenveloped single-stranded DNA virus initially implicated as a cause of posttransfusion hepatitis. Initial reports suggested a possible role in neonatal hepatitis; however, the role of TTV in contributing to liver disease has not been proven.
Reovirus-3 has been proposed as a candidate virus serving as an etiologic agent for neonatal hepatitis as well as biliary atresia. Infection of weanling mice results in hepatic lesions similar to those observed in neonates with neonatal hepatitis. However, studies in humans using molecular techniques have yielded mixed results.
Paramyxovirus infection has been attributed as the etiologic agent in a rare form of hepatitis termed syncytial giant-cell hepatitis affecting both children and adults. In neonates, syncytial giant-cell hepatitis is associated with a severe hepatitis, with progression to chronic cholestasis and decompensated cirrhosis over the first year of life. Liver histologic evaluation reveals both the hallmark of syncytial-type 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. Virus-like structures within giant cells resembling the nucleocapsids of paramyxovirus have been seen on electron microscopy. These giant cells are larger and of different morphology than the giant cells typically encountered in neonatal liver disease. The putative virus from the paramyxoviruses family has not been subsequently identified since this entity was first described.
Parasitic Infections
Toxoplasmosis
Toxoplasma gondii is an obligate intracellular protozoan parasite that can cross the placenta and infect the fetus. Congenital infection occurs primarily as a result of maternal infection during pregnancy acquired by consumption of undercooked meat or direct contact with the feces of infected animals, particularly cats. IgM screening has documented the prevalence of congenital infection to range from 2 to 8 per 10,000 live births in developed nations.
Most infants born with congenital Toxoplasma infection are asymptomatic in the neonatal period, with clinical signs and symptoms being present in only approximately 10% to 30% of infants. The most characteristic clinical findings, referred to as the classic triad of congenital toxoplasmosis, include chorioretinitis, intracranial calcifications, and hydrocephalus. Other signs and symptoms include hepatosplenomegaly, jaundice, maculopapular rash, lymphadenopathy, and thrombocytopenia. Serum aminotransferase levels are elevated, and progressive liver dysfunction with ascites may occur. Liver histopathology features include nonspecific giant-cell hepatitis with focal necrosis associated with parasitized sinusoidal cells. Congenital toxoplasmosis has been reported in a newborn with severe pneumonitis, hepatitis, and disseminated intravascular coagulation. A case of an infant with congenital toxoplasmosis presenting as isolated hepatitis has been reported recently.
The diagnosis of congenital toxoplasmosis can be made prenatally by the detection of T. gondii in fetal blood or amniotic fluid, or from the placenta, umbilical cord, or infant peripheral blood via PCR. Serologic diagnosis can be made by IgM or IgA or persistent (over 12 months) IgG anti- Toxoplasma antibody tests determined in the infant’s blood. Treatment with pyrimethamine and sulfadiazine prevents progression of organ damage.
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