Elevated serum aminotransferases in an infant with failure to thrive: A clinicopathological case report

A 6-month-old male was referred to the outpatient gastroenterology clinic for evaluation of poor weight gain. From 3 to 4 months of age, the patient's weight was noted to plateau, falling from the ninth percentile to less than the first percentile. Efforts to improve growth by increasing the infant's dietary intake were unsuccessful. The parents described the patient as a “distracted feeder” at home, only taking partial feeds of breastmilk and solids and rejecting formula from the bottle. By 4–6 months of age, it was evident that his linear growth was also failing (Figure 1) while his head circumference was increasing normally. At that point, his development was appropriate, and physical examination was only remarkable for atopic dermatitis. He was referred by his primary care physician (PCP) to pediatric gastroenterology and was seen at Age 7 months. History during the initial visit revealed that he was largely breastfed every 3 h for 20 min per feeding, and the mother would feel “pretty empty” after feeding. He had recently started eating infant pears, apples, bananas, and sweet potatoes once a day. He had been on a variety of formulas, including soy and hypoallergenic formulas, which he did not like. He would drink 2–4 oz of cow's milk protein formula while his mother pumped, producing about 4–5 oz of breast milk per pumping session. The gastroenterologist advised increased nutritional intake. Despite efforts to optimize nutrition, growth failure persisted, resulting in hospitalization for failure to thrive (FTT) at 10 months of age. By that time, he was taking gluten-containing foods. Celiac testing was negative. Inadequate caloric intake was still suspected as the primary cause based on his history and unremarkable physical examination. In alignment with parents' observations at home, while inpatient, he demonstrated inadequate oral intake. He took partial bottle feeds and had inadequate transfer of breastmilk, evidenced by pre- and post-prandial weights. The occupational therapy evaluation failed to reveal a mechanical cause of oral feeding intolerance. The therapist was reassured by adequate coordination of suck and swallow. The social worker noted missed follow-up at the FTT clinic in part due to the family living 1.5 h away from the hospital. Given his inadequate intake, a nasogastric tube (NGT) was placed on Day 3 of hospitalization. He appeared to show appropriate weight gain with PO plus Good Start Gentle 20 kcal/ounce NGT feeds containing 95 kcal/kg/day and total protein of 1.5 g/kg/day. He was admitted for 7 days with an average weight gain of 20 g per day. He was discharged with a NGT and close GI follow-up. His differential diagnoses during hospitalization included inadequate caloric intake, malabsorption, obstruction, cardiac disease, infection, and metabolic disorder, but these were deemed less likely due to reassuring vital signs, normal physical examination, typical age-appropriate development, tolerance of feeds, and demonstrated ability to gain weight. A full FTT work-up (Table 1) was unremarkable except for the finding of elevated serum aminotransferases and a mildly elevated ferritin, both of which preceded initiation of NGT feeds. The patient's parents reported an unremarkable newborn screen (California) and no family history of cystic fibrosis (CF), thus sweat chloride testing was not performed. Fecal fat and fecal elastase testing were considered but deferred, given reassuring weight gain with NGT feeds while admitted. Studies to investigate an etiology for the elevated serum aminotransferases (Table 2) were unrevealing, ruling out viral hepatitis (A, B, C, E), cytomegalovirus (CMV) infection, rhabdomyolysis, alpha-1 antitrypsin deficiency, autoimmune conditions, and various metabolic disorders (lysosomal acid lipase, lactate, and pyruvate deficiencies). An abdominal ultrasound was also obtained and was normal. Following discharge, the patient's aminotransferases worsened despite improved weight gain, prompting an outpatient liver biopsy at 21 months of age (Table 3). The liver biopsy (Figure 2) revealed portal inflammation, steatosis, and portal fibrosis. Although the biopsy lacked typical autoimmune hepatitis (AIH) findings, such as interface hepatitis and lymphoplasmacytic portal infiltrate, the patient was started on prednisolone and ursodiol pending additional studies (Table 2). Aminotransferases increased after initiating prednisolone; thus, the drug was discontinued less than 3 weeks later. During subsequent gastroenterology follow-up the next month, the patient was noted to develop multisystem anomalies, including dental caries, new-onset neutropenia (Table 4), and speech delay, leading to his referral to genetics. Whole exome sequencing (WES) was performed, and facial recognition software (face2gene)1 was utilized to identify potential genetic syndromes based on dysmorphic features. The software suggested several potential syndromes but did not include our patient's final diagnosis. The patient initially presented with growth failure. This problem has a broad differential including inadequate intake, malabsorption, maldigestion, or hypermetabolic state. Inadequate intake is most common and can be diagnosed based on history and demonstrated ability to gain weight with sufficient calories. We also considered malabsorptive etiologies such as pancreatic insufficiency (soft stools and adequate weight gain with monitoring of intake were interpreted as normal for age and breastfeeding), celiac disease (screening labs unremarkable), and early-onset inflammatory bowel disease (no history of diarrhea or blood per rectum, and inflammatory markers were normal). Examples of maldigestion, such as reflux (unlikely without frequent emesis) and intestinal obstruction (excluded by normal imaging and bowel movements; no distension or emesis), were unlikely in our patient. Increased metabolic demand can arise from congenital heart disease (the lack of cyanosis or tiring with feeds and the normal echocardiogram were all reassuring), hyperthyroidism (thyroid-stimulating hormone [TSH] and thyroxine [T4] were normal), chronic infection (labs ruled out CMV, Ebstein–Barr virus [EBV], viral hepatitis, urinary tract infection, or pneumonia), malignancy (initial blood counts normal, no other constitutional symptoms), and metabolic disorders (normal newborn screen, normal amino acids and acylcarnitines, and no vomiting, seizures, or abnormal odors), and new-onset diabetes (glucose and urinalysis reassuring), all of which were unlikely in our patient. Given his short stature, constitutional growth delay, and achondroplasia were also considered early in life (normal pelvic radiograph and bone age suggested against this). Differential diagnosis of elevated serum aminotransferases can be broken into hepatocellular injury and cholestasis. Etiologies of hepatocellular injury include (1) malnutrition, (2) viral hepatitis (A, B, C, E), (3) CMV or EBV infection, (4) rhabdomyolysis, (5) alpha-1 antitrypsin deficiency, (6) autoimmune hepatitis, (7) CF liver disease, (8) metabolic disorders (lysosomal acid lipase, lactate, and pyruvate deficiencies), and (9) Wilson disease. Etiologies of cholestatic liver injury, such as choledocholithiasis and acute cholangitis, were unlikely given disproportionate elevation of ALT and AST compared to alkaline phosphatase, normal abdominal ultrasound, and absence of abdominal pain or fevers. Malnutrition was initially deemed the most likely cause of the abnormal serum aminotransferases but proved unlikely when liver enzymes remained high despite improving weight gain and nutritional status. Viral hepatitis typically causes more significant elevations in liver enzymes, and viral testing reassures against this diagnosis. Congenital CMV infection was considered unlikely given the absence of hepatosplenomegaly, jaundice, microcephaly, or petechiae. Similarly, EBV testing and the absence of other systemic symptoms made this unlikely. There was low concern for rhabdomyolysis given non-elevated creatine kinase and normal electrolytes. Alpha-1 antitrypsin phenotype was MM, a normal variant. Ceruloplasmin level reassured against Wilson disease. Normal auto-antibodies, biopsy findings, and young age lowered suspicion for AIH; however, it is important to always consider seronegative AIH, thus it was kept on the differential. Malabsorption is said to typically present with loose, foul-smelling, greasy stools, flatulence, and inability to gain weight despite adequate intake. Prior literature,2 however, suggests that normal stool consistency and the presence of floating stools are unreliable ways to rule out malabsorption. Lastly, metabolic conditions were considered unlikely given the patient's normal newborn screen, intact appetite and energy level, lack of seizures or vomiting, and unremarkable odor. Fecal pancreatic elastase was <15, consistent with severe exocrine pancreatic insufficiency, and the patient was initiated on pancreatic enzyme supplementation. WES identified a hemizygous mutation of the Shwachman–Bodian–Diamond Syndrome (SBDS) gene on chromosome 7q11 in conjunction with a deletion of chromosome 7q11.21, which contains the SBDS gene, confirming a diagnosis of Shwachman–Diamond Syndrome (SDS) at 2.5 years of life. This case report discusses a patient who presented with poor growth as an infant and was later found to have elevated serum aminotransferases and neutropenia, with an ultimate diagnosis of SDS. Median age at diagnosis of SDS is under 1 year, with a median survival of 35 years.3 Patients with SDS frequently experience impaired growth due to exocrine pancreatic dysfunction, with about 90% of those with SBDS variants (the gene affected in our patient) showing intrauterine growth restriction or short stature.4 With proper pancreatic enzyme supplementation, growth is expected to normalize. SDS-specific growth charts can be utilized to monitor growth in this population.5 Notable physical features include skeletal abnormalities (such as chondrodysplasia), cardiac defects, dental decay, eczema, Chiari malformations, genitourinary abnormalities, and hepatomegaly.6 Interestingly, our patient was noted to have a “bell-shaped chest” on neonatal chest radiograph, which has been observed in other patients with SDS.7 Gastrointestinal defects that have been reported in patients with SDS include malrotation, imperforate anus, and bilateral inguinal hernias.6, 8 A higher rate of developmental delays has been observed among patients with SDS compared to the general population, which was noted in our patient as well.9 The main hematologic abnormality is neutropenia, but additional cytopenias can be seen. Our patient demonstrated intermittent rather than persistent neutropenia, which can be seen in some patients with SDS (Table 4). Patients are at risk for developing aplastic anemia and have an increased lifetime risk of blood cancers such as acute myeloid leukemia or myelodysplastic syndrome.6 Prior work has reported neutropenia in up to 81% of patients with SDS; bone marrow aspiration and biopsy are recommended yearly to screen for these complications.6, 7, 10 Of note, SDS shares several clinical similarities with CF including FTT due to exocrine pancreatic insufficiency and frequent infections. CF involves chronic sinopulmonary infections secondary to impaired chloride transport, while bacterial infections in SDS result from neutropenia and weakened immune function. CF lacks hematologic and skeletal abnormalities seen in SDS. It is important to distinguish these etiologies of malabsorption as unique risk factors, and screening is indicated. Patients with SDS require vigilant monitoring for bone marrow abnormalities, regular assessments of developmental and nutritional status, twice-yearly dental screening, pre-pubertal dual-energy X-ray absorptiometry scan, and close observation for orthopedic complications during growth spurts.6 SDS is most commonly inherited in an autosomal recessive manner (including those with SBDS variants such as in this patient), although rarely can have autosomal dominant inheritance.5 Counseling regarding the 25% chance of recurrence in future pregnancies is essential for family planning. Prior literature on SDS indicates a range of hepatic presentations. A recent review of 32 articles reported a spectrum of liver involvement, ranging from benign and self-resolving liver enzyme elevations to significant fibrosis and hepatic failure.3 Severe liver involvement was specifically documented in three studies.3 In another study of 37 patients with SDS, 41% were reported to have elevated serum aminotransferases, but the extent of hepatic involvement was not delineated.8 Several case reports have documented severe hepatic involvement in the first year of life. One case study described a child who presented with FTT and elevated aminotransferases and was found to have hepatic cirrhosis on biopsy by 16 months.11 In an even more severe case, an infant with SDS was found to have macronodular cirrhosis under 1 month of life.12 Furthermore, a 15-month-old who presented with FTT, hepatomegaly, and mild aminotransferase elevation ultimately developed cirrhosis, portal hypertension, and varices.13 A recent case report described a 36-year-old patient who presented with massive ascites and cirrhosis leading to a late diagnosis of SDS in adulthood.14 This highlights the importance of including SDS in the differential diagnosis of patients of all ages who present with elevated liver enzymes. The differential diagnosis evolved throughout the patient's evaluation, initially focusing on FTT, but later incorporating potential causes for elevated aminotransferases and hepatic fibrosis, including malnutrition, infections, autoimmune hepatitis, drug effects, and various metabolic disorders. This case emphasizes the importance of maintaining a broad, fluid differential for elevated aminotransferases and FTT. Loose stools are common in breastfed infants; thus did not initially raise a suspicion for malabsorptive etiology of the poor weight gain, though fortunately, they did not prevent further evaluation for pancreatic insufficiency. The absence of steatorrhea or diarrhea seen in this case has been rarely reported in SDS literature. Interestingly, while up to three-quarters of patients with SDS have FTT suggesting malabsorption, a study of 37 patients with SDS reported that only 58% of patients had diarrhea.8 Furthermore, though most had low fecal elastase, not all patients with SDS have this lab finding, suggesting the need for high index of suspicion for malabsorption when a patient has persistent growth failure.8 Another case report in 2013 outlined two cases of SDS presenting without diarrhea or malabsorption, highlighting that SDS should not be excluded from the differential based on an absence of gastrointestinal findings.15 These cases underscore the variability in presentation of multisystem conditions like SDS and the pitfalls of relying solely on symptomatic history to guide evaluation. Our case also emphasizes that when a patient has seemingly isolated, unexpected lab and exam findings, it is essential to consider a unifying genetic diagnosis. In this case, the extensive workup to identify the etiology of this infant's transaminitis and provide appropriate management required whole exome screening to establish the diagnosis of Shwachman–Diamond Syndrome. The authors would like to acknowledge the contributions of Drs. Sandeep Gupta and Neil LeLeiko in the preparation of this manuscript. The authors declare no conflicts of interest. Informed parent consent was obtained for publication of the case details.