Porphyrin precursors in urine hint at liver cancer risk in AIP: Study
Regular urinary sampling recommended for older patients with high levels
People with acute intermittent porphyria (AIP) who have high levels of porphyrin precursors in the urine are more likely to develop primary liver cancer, according to a new study that also found the risks are higher for these AIP patients after age 65.
“Individualized PLC [primary liver cancer] risk assessment is important as most patients with AIP will never develop PLC,” the researchers wrote.
However, they added, “since high and increasing [porphyrin precursor] levels were associated with increased risk of PLC in the current study, we recommend regular sampling of urinary … porphyrin precursors also in older asymptomatic patients.”
The study, “Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients,” was published in The Journal of Inherited Metabolic Disease by a team of researchers in Sweden.
Higher risks of liver cancer seen for porphyria patients in Sweden
Porphyria occurs when there’s a flaw in one of the eight steps that lead to the production of heme from porphyrins and its precursors. Heme is a component of iron-containing proteins, including hemoglobin, which carries oxygen in red blood cells.
In AIP, there’s a mutation in the gene that provides instructions for producing an enzyme responsible for the third step in the process. That mutation reduces the enzyme’s activity and limits the amount of heme that can be produced.
As a result, 5-aminolevulinic acid, known as ALA, and porphobilinogen, called PBG — the products of the first two steps in the process — build up to toxic levels in the liver and other organs. This can lead to sudden attacks of severe abdominal pain and other symptoms.
In earlier research involving many of this study’s scientists, a team observed that primary liver cancer was 38 times more likely to occur in people with acute porphyria than in the general population of Sweden. This risk was even higher for those with AIP and high levels of PBG in the urine.
To see if this also was true for ALA, the researchers now focused on 48 people with AIP who developed liver cancer between 1987 and 2015. As controls, the study also included 140 age- and sex-matched AIP patients who didn’t develop cancer.
All were in the Swedish porphyria register, a database that includes patients in the country who receive a diagnosis of the genetic disorder.
Peak levels of PBG in the urine were about twice as high in patients who developed liver cancer as compared with controls (10.9 vs. 5.1 millimoles per mole (mmol/mol) of creatinine). Also, peak levels of ALA were higher in patients who developed liver cancer (7.4 vs. 4.2 mmol/mol of creatinine).
Both measures involved creatinine, a waste product that serves as an indicator of how well the kidneys are working. Here, it was used to correct the levels of these porphyrin precursors in the urine.
None of the 29 patients whose porphyrin precursor levels were within normal levels developed liver cancer. Meanwhile, one patient among those whose levels were less than two times the upper limit of normal developed liver cancer.
Patients with normal levels appear to have a low risk while high or increasing ALA and PBG after age 65 indicates high risk, which should be considered in surveillance decisions.
Researchers also observed that ALA and PBG levels tended to decrease slowly over time in patients who didn’t develop liver cancer. However, in those who did develop this cancer, these levels increased after age 65 and in the years preceding their liver cancer diagnosis.
“Patients with normal levels appear to have a low risk while high or increasing ALA and PBG after age 65 indicates high risk, which should be considered in surveillance decisions,” the researchers wrote.
The study was support by Alnylam Pharmaceuticals, the company that markets Givlaari (givosiran), a medication approved in the U.S. to treat adults with acute porphyria. In Europe, Givlaari also is approved for the same indication in patients ages 12 and older.