Neonatal intrahepatic cholestasis caused by citrin deficiency

Alternate names

NICCD; Neonatal-onset citrullinemia type II; Citrin deficiency; Neonatal-onset citrullinemia type 2

Definition

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a liver condition is also known as neonatal-onset type II citrullinemia.

Summary

• NICCD blocks the flow of bile (a digestive fluid produced by the liver) and prevents the body from processing certain nutrients properly. This leads to transient intrahepatic cholestasis and variable liver dysfunction in children younger than one year of age.
• NICCD is generally not severe, and symptoms disappear by age one year with appropriate treatment. Years or even decades later, however, some of these individuals develop the characteristic features of adult-onset type II citrullinemia.

Cause

NICCD is caused by mutations in the SLC25A13 gene.

Inheritance

Autosomal recessive inheritance, a 25% chance

Citrin deficiency is inherited in an autosomal recessive manner. When both parents are carriers of an SLC25A13 pathogenic variant, each sib of an affected individual has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. When one parent is a carrier and the other parent has two SLC25A13 pathogenic variants, each sib of an affected individual has, at conception, a 50% chance of being affected and a 50% chance of being an asymptomatic carrier.

Signs and symptoms

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is characterized by transient intrahepatic cholestasis, diffuse fatty liver, hepatic fibrosis, low birth weight, growth retardation, hypoproteinemia, decreased coagulation factors, hemolytic anemia, hepatomegaly, variable liver dysfunction, and/or hypoglycemia in children younger than one year of age. NICCD is generally not severe, and symptoms typically disappear by age one year with appropriate treatment. At around age two, children with NICCD begin to show a particular fondness for protein-rich and fatty foods and an aversion to sugary and carbohydrate-rich foods. One of more decades later, some of these individuals develop neuropsychiatric symptoms characteristic of adult-onset citrullinemia type II.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Decreased circulating antibody level
• Elevated [[alkaline phosphatase](Greatly elevated alkaline phosphatase)
• Elevated alpha-fetoprotein
• Elevated gamma-glutamyltransferase level
• Elevated plasma citrulline
• Hyperbilirubinemia(High blood bilirubin levels)
• Hypergalactosemia
• Hypertriglyceridemia(Increased plasma triglycerides)
• Hypoalbuminemia(Low blood albumin)
• Increased lactate dehydrogenase level
• Jaundice(Yellow skin)
• Lactic acidosis(Increased lactate in body)
• Prolonged prothrombin time

30%-79% of people have these symptoms

• Abnormal circulating alanine concentration
• Abnormal circulating arginine concentration
• Abnormal circulating glutamine concentration
• Diarrhea(Watery stool)
• Elevated hepatic transaminase(High liver enzymes)
• Failure to thrive in infancy(Faltering weight in infancy)
• Hepatic steatosis(Fatty infiltration of liver)
• Hepatomegaly(Enlarged liver)
• Hepatosplenomegaly(Enlarged liver and spleen)
• Hyperammonemia(High blood ammonia levels)
• Hyperlysinemia(Elevated blood lysine)
• Hypertyrosinemia(Increased tyrosine in blood)

5%-29% of people have these symptoms

• Abnormal circulating serine concentration
• Anemia(Low number of red blood cells or hemoglobin)
• Decreased HDL cholesterol concentration(Decreased circulating high-density lipoprotein cholesterol)
• Gastrointestinal hemorrhage(Gastrointestinal bleeding)
• Hypercholesterolemia(Elevated serum cholesterol)
• Hypermethioninemia(Increased methionine in blood)
• Hyperthreoninemia(High blood threonine levels)
• Increased LDL cholesterol concentration(Increased circulating LDL level)
• Increased urinary glycerol
• Intrauterine growth retardation(Prenatal growth deficiency)
• Ketonuria
• Poor appetite(Decreased appetite)

1%-4% of people have these symptoms

• Cataract(Clouding of the lens of the eye)

Diagnosis

The diagnosis of citrin deficiency is established in an individual with characteristic biochemical findings (in general, increased blood or plasma concentration of ammonia, plasma or serum concentration of citrulline and arginine, plasma or serum threonine-to-serine ratio, and serum concentration of pancreatic secretory trypsin inhibitor) and identification of biallelic pathogenic variants in SLC25A13.

Treatment

NICCD: Supplement diet with fat-soluble vitamins and use of lactose-free and medium-chain triglyceride (MCT)-enriched formula. Use of arginine, sodium pyruvate, and MCT oil may delay the need for liver transplantation.

Agents/circumstances to avoid: Low-protein high-carbohydrate diets; glycerol and fructose infusions for brain edema; alcohol; acetaminophen and rabeprozole.

NIH genetic and rare disease info

• NIH info on Neonatal intrahepatic cholestasis caused by citrin deficiency

Neonatal intrahepatic cholestasis caused by citrin deficiency is a rare disease.

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