Neonatal cholelithiasis in Down syndrome: Is hypothyroidism involved? A case-report

1 Introduction

Down syndrome (DS) is the most common chromosomal alteration in humans with a prevalence of approximately 1 in 650 to 700 live births [1].

Many gastrointestinal complications are associated with DS including gastroesophageal reflux, constipation, motility disorders, duodenal stenosis or atresia, imperforate anus, Hirschsprung disease and esophageal atresia [2, 3].

Cholelithiasis is uncommon in the general pediatric population with an ultrasonographic prevalence no greater than 0.5% [4]. Predisposing factors include prematurity, phototherapy, parenteral nutrition, abdominal surgery, anatomic abnormalities of the biliary system, haemolytic disease, and the use of some drugs, such as diuretics, narcotic, analgesics and ceftriaxone [4]. An increased prevalence and risk of cholelithiasis has been reported in children with DS [5, 6] with only few cases in the first two years of life [7]. Cholelithiasis in DS patients has a good prognosis, and a spontaneous resolution was observed in most patients [8].

We report a case of an infant with DS, whose primary neonatal thyroid screening was negative, affected by congenital hypothyroidism (CH) and severe cholestasis with cholelithiasis and we debate this association.

2 Clinical report

An infant with DS was admitted to our hospital for jaundice and poor weight gain. He was the second child of non-consanguineous, healthy parents. Family history was negative. Pregnancy was uneventful, but delivery was by caesarean section at 38 weeks because of podalic presentation. Apgar score was 8^I –9^V. Birth-weight was 2710 gr (3^rd centile), length 48 cm (5^th centile), and occipito-frontal head circumference was 34 cm (10^th centile). DS was diagnosed at birth.

The neonatal screening for CH was negative. At the 4^th day of life he was admitted to our hospital for congenital duodenal obstruction. Parenteral nutrition was carried out for 5 days.

At the age of 7 weeks he was hospitalized again because of prolonged jaundice, and failure to thrive. His weight was 3420 gr (<3^rd centile), and his length was 54 cm (<3^rd centile). He showed jaundice, hoarse cry, and generalized hypotonia. The abdomen was distended with omphalocele. Thyroid function showed raised TSH (290 mIU/L; normal: 0.5–4.0 mIU/L), with low FT₄ concentration (5.15 pmol/L; normal: 10.29 –24.45 pmol/L). Antithyroperoxidase and antithyroglobulin antibodies were negative. Iodine urinary excretion was 61μg/L (normal range: 50 –150μg/L). Neck ultrasonography showed an in-place, normally sized thyroid gland. 99mTc-pertechnetate scintigraphy showed normal position and shape of the thyroid gland but overall slightly weak fixation. Therefore, treatment with thyroxine (8μg/Kg) was started.

ECG and echocardiography showed normal heart function and morphology. The level of liver enzymes was elevated: aspartate aminotransferase 96 U/L (normal range: 10–35 U/L), alanine aminotransferase 104 U/L (normal range: 10–35 U/L), alkaline phosphatase 685 U/L (normal range: 145–480 U/L), gamma-glutamyltransferase 2310 U/L (normal range: 10–30 U/L), total bilirubin 6.3 mg/dL (normal range: 0.1–1.2 mg/dL), direct bilirubin 3.3 mg/dL (normal range: 0.1–0.3 mg/dL). Infective hepatitis, autoantibodies, metabolic and coagulation screening tests were normal as well as lipidic profile.

Ultrasonographic hepatobiliary scanning revealed distension of bile ducts and massive debris in the extra-hepatic bile ducts, associated with the presence of gallbladder and choledochal lithiasis (Fig. 1). Dimension and echogenecity of liver were normal; there was no evidence of portal hypertension. Therefore, treatment with ursodeoxycholic acid was started with rapid improvement of the symptoms and the laboratory tests. OPEN IN VIEWER

A new ultrasonographic hepatobiliary scanning at the 4^th month of age showed normal bile ducts, but the persistence (although with significant reduction) of the gallbladder stone.

The exact pathological mechanism of cholelithiasis in DS patients remains unknown. Delayed emptying of the biliary tract, modification of bile composition and its lower excretion rate due to reduced T₄ levels have been described as possible explanations of increased association of bile duct stones and hypothyroidism [9].

Patients with DS show a high prevalence of CH if compared to the general pediatric population. Some data has also demonstrated that DS patients have isolated blood T4 lower concentrations or idiopathic mild plasma TSH elevation (4–10 mIU/l). The clinical significance of these two latter dysfunctions is still not well known today. A study performed by Bocconi et al. showed an association between DS and hypercholesterolaemia during the fetal life [10]. However, studies are needed to confirm a possible association of this condition with cholelitiasis in DS patients.

To our knowledge this is the first report of cholelithiasis in infants with Down’s syndrome and congenital hypothyroidism. CH should always be taken into consideration in these patients, especially in presence of gastrointestinal symptoms or malformations, even if their neonatal thyroid screening results are negative.

Conflict of interest disclosure

The authors exclude any conflict of interest in the work presented here.

Declaration of funding source

The authors declare that this work was not supported by research grant or other forms of financial support.