Clinical Guidance

Citrin deficiency has three age-dependent, variable clinical phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2). Citrin deficiency can manifest in newborns or infants as NICCD characterized by a diverse set of metabolic abnormalities, including citrullinemia, galactosemia, hypoglycemia, and sometimes hyperammonemia that is likely secondary to liver dysfunction. In most individuals, the clinical manifestations of NICCD improve or resolve by age 12 months. However, some individuals remain symptomatic with progression to FTTDCD, which is characterized by poor weight gain, poor linear growth, dyslipidemia, recurrent hypoglycemia, and fatigue. These individuals may have a silent remission period until after adolescence; 10%-20% evolve into the very severe or even fatal metabolic condition CTLN2, characterized by hyperammonemia, severe liver steatosis, cognitive impairment with sudden episodes of unconsciousness due to brain edema, and pancreatitis. The proportion of people with NICCD that evolve into CTLN2 is unknown. Often, FTTDCD and CTLN2 are characterized by the individual's preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD) Table 2. Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency: Frequency of Select Features

Diagnostic Criteria

Citrin deficiency has three clinical phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2) . A symptomatic individual may have either untreated NICCD due to newborn screening (NBS) not performed, false negative NBS result, caregivers not adherent to recommended treatment following a positive NBS result, or manifestations associated with later-onset citrin deficiency (FTTDCD or CTLN2).

Suggestive Findings

Scenario 1: NICCD (includes abnormal NBS result and symptomatic newborn)

Management Guidelines

Although progress has been made [, , , ], no well-recognized clinical practice guidelines for citrin deficiency have been published. The following recommendations are based on the authors' personal experience managing large cohorts of individuals with this disorder over a long period of time.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with citrin deficiency, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 7. Citrin Deficiency: Recommended Surveillance