Cholestasis and Hepatic Iron Deposition in an Infant With Complex Glycerol Kinase Deficiency

Presentation

The case was a 3100-g 6-week-old male infant transferred to our NICU for further evaluation of persistent hyperbilirubinemia, hypertriglyceridemia, elevated creatine kinase (CK) levels, and transaminitis. He was born at 40 weeks’ gestation by spontaneous vaginal delivery to a 30-year-old gravida 1 para 0 mother who was Group B Streptococcus positive but otherwise had unremarkable prenatal serologies. Apgar scores were 9 and 9 at 1 and 5 minutes, respectively, and birth weight was 2946 g. Mother received adequate intrapartum antibiotic prophylaxis but was diagnosed with chorioamnionitis; thus, the patient received 48 hours of antibiotics at birth. He was also noted to have mild jaundice in the first few days of life attributed to ABO incompatibility, although his hemoglobin levels showed no evidence of hemolysis.

On day of life 5, he became febrile, lethargic, and more jaundiced. He developed severe refractory hypotension and respiratory failure. Laboratory testing revealed a significant coagulopathy (international normalized ratio 3.9), hyponatremia, and hyperkalemia in the setting of significant oliguria. He was also noted to have signs of end-organ ischemia with an elevation in his troponins, creatinine, transaminases, and CK levels. He was managed with broad-spectrum antibiotics for presumed sepsis, and with multiple vasopressors and hydrocortisone for his refractory hypotensive shock. He received intramuscular vitamin K and fresh-frozen plasma transfusions over several days until normalization of his international normalized ratio.

Extensive infectious workup, including bacterial, viral, and fungal studies, remained negative. He slowly improved and was weaned from the ventilator and all blood pressure support, including steroids. All laboratory values normalized with the exception of his direct bilirubin, CK levels, and transaminases, with his aspartate aminotransferase and alanine aminotransferase showing a persistent fivefold elevation despite discontinuation of parenteral nutrition. He was further noted to have elevated triglyceride levels up to maximum of 811 mg/dL despite being fed several different types of formula.

Given the continued elevation in his bilirubin and transaminases, he received an extensive gastrointestinal workup, including normal abdominal imaging (ultrasound and upper gastrointestinal series), normal pancreatic enzyme and ammonia levels, and negative hepatitis serologies. A hepatobiliary iminodiacetic acid scan conducted at 1 month of life revealed no excretion of tracer from the liver; thus, a liver biopsy was done, which revealed focal intracellular cholestasis with giant cell transformation of some hepatocytes and moderately increased iron stores, but no steatosis, fibrosis, necrosis, inflammation, or features of biliary atresia. The hepatic siderosis raised concerns for neonatal hemochromatosis, a phenotype of severe liver disease with extrahepatic iron deposition that can result from various causes.⁴ Our patient underwent a buccal biopsy to look for iron staining and a brain MRI to look for iron deposition, but these were both normal. He was evaluated for inborn errors of metabolism that can cause liver disease, such as galactosemia, tyrosinemia, or α-1 antitrypsin deficiency, and was found to have borderline elevated levels of acylcarnitines known to be falsely elevated by parenteral nutrition. Otherwise this workup was negative.

Given the persistent laboratory abnormalities, transfer to our NICU was requested. On admission, he was clinically stable, but his weight was below the third percentile, down from the 15th percentile at birth. Examination revealed cryptorchidism, scleral icterus, and mild hypotonia, but notably no hepatomegaly. He also had extremely dark skin, which the parents reported was not present at birth but had developed quickly after birth. The remainder of the examination was normal. Laboratories in the first week of admission revealed normal electrolytes but continued hypertriglyceridemia, cholestasis, transaminitis, and CK elevations (Table 1). We investigated for inborn errors of bile acid metabolism by sending total and fractionated bile acid levels, as elevations of unusual bile acids have been associated with severe cholestasis and subsequent liver damage.^5,6 Although our patient’s total bile acid levels were elevated (>128 μmol/L), his profile indicated nonspecific cholestasis given the predominance of primary bile acids.

Over the next 2 weeks, he remained hospitalized working on oral feeds. Routine laboratories at 7 weeks of age revealed hyponatremia (130 mmol/L) and hyperkalemia (8.1 mmol/L) with normal renal function (creatinine 0.18 mg/dL) and good urine output on full enteral feeds and no medications. Although he remained hemodynamically stable, his ongoing lack of a unifying diagnosis and these laboratory findings led to an investigation of his adrenal function. Both his cortisol (2.0 μg/dL) and aldosterone (<3.0 ng/dL) levels were abnormally low. Concurrent plasma adrenocorticotropic hormone and plasma renin activity levels were noted to be extremely elevated at 3192 pg/mL (normal 5–46 pg/mL) and 66 ng/mL per hour (normal for age <37 mg/mL per hour), respectively. Combining this evidence of adrenal hypofunction with his elevated CK levels, complex GKD was suspected. The laboratory was asked to correct his triglyceride levels for serum glycerols, which revealed a true triglyceride level within the normal range. Furthermore, glycerol kinase levels were confirmed to be elevated at 4384 μmol/L (normal 13–66 μmol/L).

Ultimately, a comparative genomic hybridization microarray study was done, which confirmed an Xp21 deletion (Table 2). His mother was also found to be a carrier of this deletion by fluorescence in situ hybridization study.

Our patient was started on replacement fludrocortisone and hydrocortisone; within 4 days, his plasma renin activity levels normalized. Over the course of the next few weeks, his hyperpigmentation, feeding skills, and weight gain also improved and he was discharged from the hospital.