Sindromul de atrezie biliară asociată cu malformaţie splenică – o formă rară de atrezie de căi biliare, cu posibilă evoluție favorabilă

Introduction

Biliary atresia (BA) is a progressive inflammatory and fibrosclerosing disease of the biliary system that can lead to end-stage liver disease. Its incidence ranges from approximately 1 in 8000 to 1 in 18,000 live births⁽¹⁾. BA is characterized by persistent cholestatic jaundice during the neonatal period and is the most common surgical cause of cholestatic jaundice in newborns. However, about 10% of infants with biliary atresia present with additional congenital anomalies. This distinctive subgroup, commonly referred to as biliary atresia with splenic malformation (BASM) syndrome, exhibits splenic abnormalities (polysplenia, double spleens, or asplenia), with or without situs inversus, preduodenal portal vein, absent inferior vena cava, malrotation, and cardiac anomalies^(2,3). These complex abnormalities suggest that BASM syndrome arises during embryonic development and is, therefore, classified as the embryonic or syndromic form of BA. Currently, timely Kasai portoenterostomy (KPE) is considered the standard treatment. However, liver transplantation may be required if the KPE fails to restore the biliary flow or if complications related to cirrhosis develop⁽⁴⁾.

Case report

We present the case of a female neonate with a birth weight of 3260 grams, born at 37 weeks of gestation to a mother with pregestational insulin-dependent diabetes mellitus. During prenatal care, obstetric ultrasound revealed complex cardiac abnormalities: heterotaxy, interrupted inferior vena cava with continuation of the azygos vein, and partial anomalous pulmonary venous return to the inferior vena cava. The newborn was admitted to the neonatal intensive care unit for the management of the prenatally diagnosed congenital anomalies.

The neonate presented jaundice, pale stools and dark urine. In addition, the physical examination revealed dysmorphic facial features (broad nasal root, low-set ears and hypertelorism), hepatomegaly and splenomeg­aly. The laboratory findings showed a hemoglobin level of 17.2 g/dL, direct hyperbilirubinemia (total bilirubin of 9.64 mg/dL, direct bilirubin of 4.15 mg/dL), cholestasis (increased GGT to 714 U/L and ALP 236 U/L), normal transaminases (ALT 29 U/L, AST 18 U/L) and albumin levels (3.4 g/dL). These results were suggestive of obstructive cholestasis. Infectious causes of neonatal cholestasis, including toxoplasmosis, rubella, cytomegalovirus and herpes, were excluded.

The abdominal ultrasound revealed situs inversus, with a normal liver echogenicity and size, while the gallbladder and the biliary ducts were not visualized. Echocardiography showed complex cardiac malformations, including an atrial septal defect of the sinus venosus type, interrupted inferior vena cava with continuation of the azygos vein, and partial anomalous pulmonary venous return to the inferior vena cava. CT angiography demonstrated symmetric hepatic tissue on both sides of the spine, with the stomach located on the right side and polysplenia in the right hypochondrium. The gallbladder and biliary ducts were absent, in addition to the previously described cardiac anomalies. The electrocardiogram showed mild bradycardia (105 beats per minute) and an inferior atrial rhythm in the context of left isomerism. The clinical and radiological findings were highly suggestive of BASM syndrome.

Surgery was performed at 3 weeks of age. Intraoperatively, heterotaxy was confirmed; the liver was cirrhotic, the gallbladder was hypoplastic, and the common hepatic, right hepatic and left hepatic ducts were atretic. The atretic gallbladder and portal plate were dissected, and a KPE was performed. The histology results were consistent with biliary atresia. The patient received steroid therapy in the postoperative period until discharge. She experienced an episode of acute cholangitis associated with hemodynamic instability, which required specific therapeutic measures and maintenance under endotracheal intubation for six days. The remainder of her recovery was uneventful. Her stools gradually regained normal color, and the liver function improved. She is currently on regular follow-up.

Discussion

Biliary atresia is an idiopathic, destructive and inflammatory cholangiopathy, affecting both intrahepatic and extrahepatic bile ducts. It leads to fibrosis, biliary tract obliteration and eventual end-stage liver disease. The most widely used classification, established by the Japanese Association of Pediatric Surgeons, categorizes BA into three types, based on the most proximal level of extrahepatic bile duct obstruction. The most common type (>90%) is type 3, characterized by proximal atresia extending to the porta. Type 1 involves atresia of the common bile duct, often associated with a proximal biliary cyst. Type 2 features atresia of the main hepatic duct with patent right and left hepatic ducts^(5,6). Another classification, proposed by Davenport, divides biliary atresia into four clinical groups: syndromic biliary atresia, cystic biliary atresia, CMV-associated biliary atresia, and isolated biliary atresia. BASM syndrome represents the syndromic or embryonal form of BA and includes a combination of biliary atresia, splenic anomalies (commonly polysplenia), vascular anomalies (such as a preduodenal portal vein and absence of the inferior vena cava), visceral asymmetry (typically situs inversus), pancreatic anomalies (including annular pancreas and pancreatic hypoplasia), and congenital heart defects^(6,7). The most frequent cardiac malformations in BASM include atrial and ventricular septal defects, patent foramen ovale, patent ductus arteriosus, coronary sinus dilation, and tetralogy of Fallot⁽⁸⁾.

Situs conditions are classified into three types: (1) situs solitus, where the organs are arranged in their normal anatomical position; (2) situs inversus, characterized by a complete reversal of organ positioning, creating a mirror image of the normal anatomy; and (3) situs ambiguous, which involves visceral malpositioning, morphological abnormalities, and indeterminate atrial arrangement (Figure 1). Situs inversus totalis refers to the complete mirroring of the standard visceral arrangement with the heart in a right-sided position (dextrocardia). On the other hand, if the situs inversus is not complete, with the heart in its usual position, then this condition is called isolated levocardia^(9,10). This entity frequently correlates with severe cardiovascular anomalies due to the heart’s atypical positioning relative to other organs and their vascular connections⁽¹¹⁾. Heterotaxy syndrome (also known as situs ambiguous) disrupts visceral organ arrangement, particularly the heart and major vessels. It includes two types of isomerism: left isomerism, characterized by bilateral left atrial morphology, bi-lobed lungs, polysplenia and elongated bronchi; and right isomerism, with bilateral right atrial morphology, tri-lobed lungs, asplenia and shortened bronchi. Both forms involve midline liver positioning, intestinal malrotation and congenital heart defects, which are more severe and potentially life-threatening in right isomerism^(12,13).

BASM syndrome is classified as syndromic, as it is considered a consequence of pathological processes occurring during the embryologic development of organs. Defective canalization during the sixth week of development, following the extrahepatic bile duct’s emergence from the intestinal primordial bud in the fifth week, results in biliary atresia. This hypothesis may also explain other components of BASM syndrome, as the biliary developmental timeline, overlap with visceral situs determination, splenic formation, and the development of venous system anomalies^(15,16). Many infants with BASM syndrome exhibited first-trimester abnormalities or complications, including a higher incidence of in vitro fertilization and maternal diabetes. Both factors are linked to an increased risk of congenital anomalies, with some overlap in specific defects, such as transposition of the great arteries^(7,15). In our patient, maternal diabetes could be a potential cause of her condition. The teratogenic mechanism of maternal diabetes remains unclear, although the proposed hypotheses include hyperglycemia, hypoglycemia and trace element deficiencies, such as zinc⁽¹⁷⁾. Another hypothesis for this syndrome is represented by genetic defects. Two mutations linked to this disease were described: CFC-1, responsible for visceral and somatic symmetry, and PKD1L1, which encodes a protein essential for primary ciliary calcium signaling, with loss-of-function mutations leading to heterotaxy^(18,19).

KPE is a palliative surgery designed to restore bile flow and delay cirrhosis progression, when performed in early infancy. Timely diagnosis and treatment are crucial in preventing liver cirrhosis, though most children with biliary atresia ultimately require liver transplantation⁽⁵⁾. Previously, BASM syndrome had poorer outcomes than isolated BA, likely due to its earlier onset. Infants with BASM also faced higher rates of postoperative complications and worse prognosis, possibly due to fewer exposed biliary ductules at the transacted portal plate or underlying liver abnormalities^(7,20). The poor prognosis in BASM may also stem from the challenges of KPE, especially with situs inversus, malrotation and vascular anomalies. Outcomes largely depend on cardiovascular lesion severity, potentially influencing surgical decisions. However, studies have shown that careful follow-up and improved imaging, planning and surgical expertise may help the BASM outcomes approach those of isolated BA, especially if the cardiac defect is not severe^(21,22). Early intervention played a crucial role in improving our patient’s outcomes.

After a KPE, many patients develop postoperative complications common to both BA and BASM, including cholangitis, portal hypertension with variceal bleeding, intrahepatic biliary cyst formation, malabsorption and nutritional deficiencies, all of which may impact the survival⁽⁵⁾. Hepatopulmonary syndrome (HPS) and portopulmonary hypertension are less common complications of biliary atresia associated with portal hypertension. In BASM, significant HPS can develop without evident cardiac malformations, sometimes resulting in sudden death. This may stem from a higher incidence of pulmonary arteriovenous malformations, potentially an intrinsic but poorly reported feature of the syndrome^(7,22,23).

On the other hand, patients with BASM syndrome may experience complications in relation to their complex anomalies. Congenital heart diseases are associated with heart failure, arrhythmias, pulmonary hypertension and infective endocarditis. They are also at risk for developmental delays affecting motor, cognitive and psychosocial functions⁽²⁴⁾. Asplenia or functional hyposplenism can lead to immunodeficiencies and greatly increase the risk of sepsis, necessitating antimicrobial prophylaxis and urgent evaluation in case of fever. While intestinal rotation abnormalities are common in patients with visceral asymmetry, volvulus is rare, and its surgical correction involves a considerable risk. Additionally, some patients experience chronic lung disease and should undergo screening for primary ciliary dyskinesia, a disorder of respiratory cilia dysfunction that can lead to bronchiectasis⁽²⁵⁾. The numerous comorbidities and complications linked to the disorder highlight the need for optimal care and regular monitoring.

Conclusions

BASM syndrome is a rare form of biliary atresia associated with complex anomalies. It has different causes and a worse prognosis than isolated biliary atresia. The syndrome can lead to end-stage cirrhosis and liver failure if left untreated, therefore timely KPE is considered the standard treatment. Early diagnosis and treatment are essential in the management of these cases. Moreover, the patients need careful follow-up to improve the outcomes.

Autor corespondent: Alina Grama E-mail: gramalina16@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

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