HISTORY OF PRESENT ILLNESS
A 2-month-old girl was referred to your hospital for evaluation of her jaundice and poor weight gain. Her father felt that she “has been yellow her whole life,” starting before she left the newborn nursery. Except for some nasal congestion, the baby seems to be acting and sleeping normally. She has been feeding on cow’s milk formula, taking about 2-3 oz every 3 hours, and making 5-6 wet diapers a day. The father describes the baby’s stool output as 2-4 “loose” and “pasty” bowel movements a day. There is no history of fever, emesis, diarrhea, travel, or unusual exposures.
The baby was the 3.25 kg product of a term gestation, delivered via cesarean section to a mother with a history of osteoporosis and back pain. The mother took no medications and denied drug and alcohol use during pregnancy. The baby was discharged home with her mother on the second day of life. Her newborn screen was normal.
She lived at home with both parents. There was no family history of cystic fibrosis, cardiac or gastrointestinal disease, or other pediatric illnesses.
T 37.2°C; HR 120 bpm; RR 28/min; BP 80/56 mmHg; Weight 3.9 kg (5th percentile); Length 53 cm (2nd percentile); Head Circumference 37 cm (15th percentile)
The infant appeared small but comfortable in her father’s lap. She had an open, flat fontanelle, and a broad forehead; equal and round pupils and scleral icterus. The oropharynx was clear with moist mucous membranes. Respirations were clear and unlabored. Cardiac examination revealed a II/VI systolic murmur loudest at the left sternal border; the rate, rhythm, and distal pulses were all normal. Her abdomen was soft and nondistended with a smooth liver edge palpable 3 cm below the right costal margin; no spleen or other masses were appreciated. The genitourinary, extremity, and neurologic examinations were all normal.
INITIAL DIAGNOSTIC STUDIES
Complete blood count: WBCs, 16 700/mm3 (neutrophils: 31%, lymphocytes: 61%); hemoglobin, 9.6 g/dL; platelets, 625 000/mm3. Serum electrolytes: blood urea nitrogen, 26 mg/dL; creatinine, 1.1 mg/dL; otherwise normal. Liver function tests: total bilirubin, 11.0 mg/dL; unconjugated bilirubin, 8.0 mg/dL, conjugated bilirubin, 3.1 mg/dL; ALT, 190 U/L; AST, 94 U/L; albumin, 3.0 mg/dL; alkaline phosphatase, 450 U/L. Blood and urine cultures, negative. Evaluations for toxoplasmosis, rubella, cytomegalovirus, and human immunodeficiency virus: negative.
COURSE OF ILLNESS
The baby was admitted to the hospital for further evaluation. A renal ultrasound showed two somewhat small but otherwise unremarkable kidneys, and biochemical measures of her renal function (e.g., BUN, creatinine) trended toward normal during the hospitalization without specific therapy. Echocardiography revealed a structurally normal heart. She had an abdominal ultrasound which showed an enlarged liver but no masses. Hepatobiliary scintigraphy (diisopropyl iminodacetate [DISIDA] scan) was done which showed normal tracer uptake but delayed intestinal excretion of the tracer at 4 and 24 h. Given those findings, she underwent immediate cholangiography and liver biopsy. The biopsy showed prominent cholestasis, occasional giant hepatocytes, and a ratio of bile ducts to portal tracts of about 0.5 (normal is around 0.9-1.8). The cholangiogram was normal. The infant had facial features (Figure 15-12) and radiograph findings (Figure 15-13) typical of this condition.
FIGURE 15-12. Photograph of a child with the same condition as the case patient. Note the wide forehead, bulbous nose, and pointed chin. (Courtesy of Dr. David Piccoli, The Children’s Hospital of Philadelphia.)
FIGURE 15-13. Butterfly vertebrae that are characteristic of this condition. (Courtesy of Dr. David Piccoli, The Children’s Hospital of Philadelphia.)
DISCUSSION CASE 15-6
This infant presents with a conjugated hyperbilirubinemia and delayed excretion on the hepatobiliary scan. While numerous etiologies may cause neonatal cholestasis, the abnormal hepatobiliary scintigraphy raises immediate concern for an obstructive process, such as extrahepatic biliary atresia. Diagnosis is usually made by cholangiography, which may detect an extrahepatic obstruction, and liver biopsy, which often reveals proliferation of bile ducts, expanded portal tracts, and bile duct plugs. Treatment of extrahepatic biliary atresia (EHBA) by hepatic portoenterostomy (Kasai procedure) is most successful when performed in the first 10-12 weeks of life, so prompt diagnosis and referral to an appropriate surgical center is essential. Even in cases where hepatic portoenterostomy is performed in a timely manner, many patients with EHBA will develop severe liver dysfunction and require liver transplantation.
Normal tracer excretion on a hepatobiliary scan supports bile ducts patency. However, failure to demonstrate hepatic excretion is not diagnostic for biliary atresia. While EHBA must always be considered, the patient had a normal cholangio-gram with evidence of bile duct paucity instead of proliferation. Interlobular bile duct paucity is the characteristic, but not unvarying, pathologic finding in Alagille syndrome. In addition, so-called “nonsyndromic” bile duct paucity can be a feature of congenital infections (e.g., CMV, rubella, syphilis), metabolic disorders (e.g., alpha-1-antitrypsin deficiency, defects of bile acid synthesis), sclerosing cholangitis, and idiopathic cholestasis.
As part of an extensive evaluation, the baby was seen by a geneticist who noted hypertelorism and a pointed mandible (Figure 15-11), in addition to the broad forehead noted on initial examination. The recommended ophthalmologic examination revealed the baby to have posterior embryotoxon, and a review of her admission chest X-ray detected butterfly vertebrae. The baby’s constellation of clinical and pathologic findings led to a diagnosis of Alagille syndrome (AGS).
INCIDENCE AND PATHOLOPHYSIOLOGY
Alagille syndrome (also known as syndromic bile duct paucity or arteriohepatic dysplasia) is an uncommon disorder associated with intrahepatic bile duct paucity as well as anomalies of the heart, eyes, kidneys, and skeleton. The disease was first described by Alagille in 1969. Since then more than 600 cases have been reported. The inheritance is autosomal dominant though many cases appear to arise from new mutations. The disease has been mapped to chromosome 20p12, specifically to mutations in Jagged1 (JAG1), a ligand in the Notch signaling pathway that is important in determining cell fate during embryogenesis. Mutations in NOTCH2, the gene for the Notch2 receptor, have also been described. There is wide variability in gene expression in AGS and even patients with identical mutations can have very different features of the syndrome.
Alagille syndrome has many manifestations, ranging from subclinical to life-threatening disease that can affect numerous organ systems. The clinical features are summarized in Table 15-11. Although presentation of the disease varies, most patients present with cholestasis in the first months of life. Clinical and laboratory findings of the liver disease include jaundice, hepatomegaly, acholic stools, pruritus, growth failure, conjugated hyperbilirubinemia, and elevations of hepatic enzymes and bile salts. Patients may have mild cholestasis or can progress to portal hypertension, cirrhosis, or liver failure. Bile duct paucity was once considered the hallmark of Alagille syndrome. However, liver biopsies on infants younger than 6 months of age may not yet demonstrate bile duct paucity, and may even show bile duct proliferation. Additionally, an increasing number of patients have been identified with “nonhepatic” AGS, where paucity is never evident and other clinical features predominate (Table 15-11).
TABLE 15-11. Clinical manifestations of Alagille syndrome.
Most patients with Alagille syndrome have heart murmurs and the underlying heart conditions range in severity from benign (e.g., mild peripheral pulmonary stenosis) to complex disease requiring surgery (e.g., tetralogy of Fallot). Intracardiac disease is a predictor of poor outcome in AGS and accounts for most early mortality in the syndrome.
Facial and ocular findings are also common characteristics of Alagille syndrome. Patients with AGS often have a distinctive facies that may be detectable as early as infancy. Features can include a triangular face with a broad forehead and pointed chin, deeply set eyes, and a long nose with a bulbous tip (Figure 15-12). The most common ocular finding is posterior embryotoxon, a dysgenesis of the anterior chamber of the eye (best seen on slit-lamp examination) in which there is prominence of Schwalbe ring, a ridge of collagenous fibers surrounding the periphery of Descemet membrane.
Skeletal problems are common, particularly abnormalities such as butterfly vertebrae (Figure 15-13). Other problems associated with Alagille syndrome include renal anomalies (both structural and functional), pancreatic insufficiency, intracranial hemorrhage, and cognitive impairments. Xanthomas are another common physical finding (Figure 15-12).
Patients known or suspected to have Alagille syndrome require a multidisciplinary initial assessment. Early evaluation and follow-up by specialists in gastroenterology and nutrition is critical. In addition, cardiology and ophthalmology evaluations should be performed as early as possible.
Liver biopsy. Diagnosis is based on the histopathologic demonstration of bile duct paucity on liver biopsy specimens in the setting of well-recognized clinical associations as described above.
Chest radiograph. X-rays of the chest are necessary to assess for vertebral anomalies (“butterfly” vertebrae and hemivertebrae).
Ophthalmologic evaluation. Ophthalmologic evaluation detects posterior embryotoxon.
Echocardiogram. Recognized cardiac involvement includes peripheral pulmonary artery stenosis and tetralogy of Fallot.
Genetic consultation. As previously noted, most patients afflicted with Alagille syndrome have a characteristic facial appearance. As such, early evaluation by a geneticist can help guide diagnosis and provide appropriate genetic counseling. In addition, genetic testing is now available for Jagged1 and NOTCH2 mutations. Recent advances in genetic testing have improved diagnosis of the disease and JAG1 mutations have been found in 94% of patients with AGS.
Treatment of Alagille syndrome focuses on the medical management of cholestasis, promotion of growth and development, and treatment of any comorbidities (e.g., congenital heart disease). Children with Alagille syndrome suffer from malabsorption and require supplementation of fat-soluble vitamins and provision of sufficient calories for growth, which may require tube feeding. Infants should receive formulas containing medium chain triglycerides, which are absorbable without bile salts. Medications that may benefit Alagille patients (e.g., by promoting bile flow, reducing pruritus, etc.) include phenobarbital, cholestyramine, ursodeoxycholic acid, and anti-histamines.
Long-term follow-up of patients with Alagille syndrome includes monitoring for the development of cirrhosis, portal hypertension, ascites, and liver failure. Twenty-year life expectancy for patients with Alagille syndrome is about 75% overall, though rates are lower for those who require liver transplantation and those with severe associated abnormalities, such as complex congenital heart disease.
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