Alternative titles; symbols
SNOMEDCT: 771441005; ORPHA: 276405;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p13 | Hyperbiliverdinemia | 614156 | Autosomal dominant; Autosomal recessive | 3 | BLVRA | 109750 |
A number sign (#) is used with this entry because hyperbiliverdinemia (HBLVD) can be caused by heterozygous or homozygous mutation in the gene encoding bilirubin reductase-alpha (BLVRA; 109750) on chromosome 7p13.
Hyperbiliverdinemia can manifest as green jaundice, which is a green discoloration of the skin, urine, serum, and other bodily fluids, due to increased biliverdin resulting from inefficient conversion to bilirubin. Although rarely reported, affected individuals appear to have symptoms only in the context of obstructive cholestasis and/or liver failure. In some cases, green jaundice can resolve after resolution of obstructive cholestasis. Green jaundice has also been associated with malnutrition, medication, and congenital biliary atresia (summary by Huffman et al., 2009).
Gafvels et al. (2009) reported a 63-year-old Swedish man with alcoholic liver failure and hyperbiliverdinemia manifested as green jaundice. The patient first presented with fatigue, weight, loss, and nausea, and laboratory studies showed elevated liver enzymes with normal serum levels of bilirubin. He had a history of cholecystectomy and of heavy alcohol consumption. He developed bleeding esophageal varices, ascites, cirrhotic liver failure, and fatal encephalopathy. During the final months of his life, he had green-tainted skin, sclerae, urine, and ascitic fluid. Liquid chromatography and mass spectrometry identified the green plasma and urine component as unconjugated biliverdin, which was significantly increased compared to controls.
Nytofte et al. (2011) reported 2 unrelated Inuit women from Greenland with episodic hyperbiliverdinemia and green jaundice. Both presented with obstructive cholestasis due to multiple gallstones; 1 was pregnant at the time. A green color developed in the skin, urine, serum, and bile, and in the milk from the pregnant woman. Laboratory studies showed increased liver enzymes and biliverdin in bodily fluids, but only 1 had increased serum bilirubin. The green discoloration resolved in both patients after surgical resolution of cholestasis. Nytofte et al. (2011) concluded that biliary obstruction was the primary event, and green jaundice appeared as a consequence.
In a 63-year-old Swedish man with liver failure and hyperbiliverdinemia manifest as green jaundice, Gafvels et al. (2009) identified a heterozygous truncating mutation in the BLVRA gene (R18X; 109750.0001). His 2 children were also heterozygous for the mutation but had no clinical signs of liver disease and had normal levels of serum biliverdin. Gafvels et al. (2009) noted that the green jaundice in this patient was only apparent in the context of liver decompensation.
In 2 unrelated Inuit women from Greenland with episodic hyperbiliverdinemia associated with obstructive cholestasis due to gallstones, Nytofte et al. (2011) identified a homozygous truncating mutation in the BLVRA gene (S44X; 109750.0002). Family study of 1 of the women showed that each unaffected parent was heterozygous for the mutation. The patient's sister, who was also homozygous for the mutation, did not have green jaundice or biliary obstruction but did have a solitary stone in the gallbladder and had biliverdin concentrations 3-fold higher than controls. The findings indicated that complete loss of BLVRA activity is a nonlethal condition.
Gafvels, M., Holmstrom, P., Somell, A., Sjovall, F., Svensson, J.-O., Stahle, L., Broome, U., Stal, P. A novel mutation in the biliverdin reductase-A gene combined with liver cirrhosis results in hyperbiliverdinaemia (green jaundice). Liver Int. 29: 1116-1124, 2009. [PubMed: 19580635] [Full Text: https://doi.org/10.1111/j.1478-3231.2009.02029.x]
Huffman, C., Chillag, S., Paulman, L., McMahon, C. It's not easy bein' green. Am. J. Med. 122: 820-822, 2009. [PubMed: 19699374] [Full Text: https://doi.org/10.1016/j.amjmed.2009.03.021]
Nytofte, N. S., Serrano, M. A., Monte, M. J., Gonzalez-Sanchez, E., Tumer, Z., Ladefoged, K., Briz, O., Marin, J. J. G. A homozygous nonsense mutation (c.214C-A) in the biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis. J. Med. Genet. 48: 219-225, 2011. [PubMed: 21278388] [Full Text: https://doi.org/10.1136/jmg.2009.074567]