Researchers from the University of Minnesota College of Veterinary Medicine (CVM) recently led a study documenting the first confirmed cases of hereditary biliverdinuria in non-human mammals. This rare metabolic disorder was identified in two adult mixed-breed dogs with persistently green urine—a hallmark of biliverdinuria. 

Green urine is typically temporary and caused by certain things like medications or infections. However, in very rare cases, the green urine is not temporary but happens persistently because of an inherited genetic condition where green pigment, biliverdin, accumulates in the body. Until now, this long-term type of green urine, hereditary biliverdinuria, had only been seen in a few humans.

Dr. Eva Furrow, associate professor of internal medicine and co-director of the Minnesota Urolith Center, was tapped to help when a dog was seen at Colorado State University Veterinary Teaching Hospital who had lifelong green urine—something Furrow had never encountered before, despite her expertise and many years of experience with urinary disorders.

As fate would have it, shortly after, she heard about a similar case of a dog at the West Los Angeles Animal Hospital in California. Intrigued, she and a multi-institutional team began digging into what was known about the condition. But the existing research was scarce, to say the least, with biliverdinuria having only been documented in a handful of human cases.

The condition is caused by defects in a gene called BLVRA, which provides instructions for making an enzyme called biliverdin reductase A. This enzyme has an important job in the body: It helps break down old red blood cells by converting a green-colored substance called biliverdin into a yellow-colored substance called bilirubin. When the enzyme doesn’t work properly, biliverdin builds up, leading to unusual and strikingly green-hued urine.

Furrow worked with a collaborative team to conduct metabolic screening and whole genome sequencing on samples from the two dog cases. Furrow’s analysis revealed different mutations in each of the dogs. In both cases, the mutations were deletions, meaning that the dogs were missing sections of the gene. This information helps identify portions of DNA that are likely critical to enzyme function.

The team was also able to conclude that the condition is likely benign. While one of the dogs also had anemia, it appeared to be unrelated to the genetic roots of biliverdinuria. 

”We were relieved to find that this genetic condition doesn’t seem to cause major disease,” Furrow reported. 

The researchers’ findings were able to give the two dogs’ families peace of mind that the unnerving urine color wasn’t linked to another problem. The research also holds significance well beyond outcomes for the two patients themselves.

“With such a rare disease every case gives us valuable information—and because of their genetic similarity, what we learn in dogs can help us understand the condition in humans as well,”  Furrow says.

The team’s work also highlights the importance of genomic tools in uncovering rare genetic disorders in veterinary medicine. 

“Newer technologies, like whole genome sequencing, have become so much more affordable in recent years. So now we can apply them to help reach diagnoses in our patients with suspected hereditary diseases. This is decreasing the number of unsolved mysteries and helping to predict outcomes for our patients and their relatives,” Furrow says. 

Furrow and members of this research team, including Dr. Steve Friedenberg, offer whole genome sequencing and analysis through the Canine Genetics Laboratory to provide other veterinarians with the ability to use this technology to help their patients.

Find the full study in the journal Genes.