FROM BLOOD
Using deferasirox to induce iron deficiency may improve the symptoms of congenital erythropoietic porphyria.
The findings come from a study of a woman of Alaskan Native descent who was diagnosed as an infant with CEP and had compound heterozygosity for C73R and A104V mutations in uroporphyrinogen III synthase. Her disease complications included chronic hemolysis and severe photosensitivity with scarring, which were managed with sun avoidance and supportive measures including blood transfusions.
With an episode of occult gastrointestinal bleeding, the patient reported a dramatic improvement in photosensitivity and a normalization in urine color. “Markers of hemolysis also improved, with a reduction in lactate dehydrogenase (LDH) level to 138 U/L and a marked reduction in circulating nucleated red blood cells (nRBCs) to 0.2 × 103 cells/mL. Hemoglobin level increased from 6.9 to 9.4. Reticulocyte count decreased to 55 billion cells/L.”
When the GI bleeding resolved, the patient’s serum ferritin level rose to 208 ng/mL, her photosensitivity worsened, and her urine color darkened. “Similarly, her LDH level increased to 540 U/L, reticulocyte count increased markedly to 163 billion cells/L, and nRBCs increased to 4.3 x 103 cells/mL.”
The researchers initiated a trial of deferasirox initially dosed at 500 mg daily for several months and then adjusted to 500 mg three times weekly to target a ferritin level range of 10-15 ng/mL. “With deferasirox, [her] serum ferritin level dropped to 16 ng/mL at 2 months and the patient again reported an improvement in her quality of life with reduced photosensitivity.” Also, total urine porphyrins decreased from 108,364 mcg/24 hours before treatment to 5896.3 mcg/24 hours after 4 months. Concurrently, LDH normalized to a level of 135 U/L, reticulocyte count decreased to 47 billion/L, nRBCs remained between 0.14 and 0.68 × 103 cells/mL, and hemoglobin level remained between 6.8 and 9.0 g/dL without transfusional support.
Upper GI bleeding recurred, however, so deferasirox was discontinued and red blood cell transfusions were administered. “Over the ensuing 2 years, numerous repeat endoscopies showed persistent gastric erosions and ulcerations despite ongoing use of a proton pump inhibitor.” As a result of the ongoing iron losses, ferritin levels remained within normal range and symptoms and laboratory markers of hemolysis were stabilized.
When the GI bleeding resolved, the patient’s lab values and her photosensitivity suddenly worsened.
Although not known to be a complication of congenital erythropoietic porphyria, the patient developed liver disease of unknown etiology and she died at age 35 of complications of liver failure, hepatorenal syndrome, and hemolysis after nearly 3 years of reduced symptom severity “and a considerable improvement in her quality of life,” Dr. Daniel N. Egan of the University of Washington, Seattle, and his colleagues reported in the case study in Blood (2015;126:257-261).
“Microscopic examination of the liver at autopsy demonstrated areas of marked sinusoidal congestion and dilatation containing aggregates of erythroid precursors consistent with diffuse intrasinusoidal extramedullary hematopoiesis. Extensive patchy fibrosis was present, without regenerative nodules or cirrhosis. Importantly, there was no evidence of polarizable material to suggest porphyrin metabolite accumulation.”
The patient’s sister, who had the same disorder, also died “from sudden cardiac death in the setting of pulmonary hypertension.”
The researchers obtained bone marrow cells from both sisters and cultured the cells in 5% plasma and varying ratios of holo-transferrin (holo-Tf) and apo-transferrin (apo-Tf) (Sigma). The level of available iron was 1.52 mcM with 100% apo-Tf and 9.52 mcM with 100% holo-Tf.
“Erythroid cells obtained from the bone marrow of this CEP patient demonstrated improved growth and differentiation in conditions of relative iron deficiency,” the authors wrote. “The percentages of normal cells reaching stages III and IV at culture day 10 progressively decreased from 67.2% to 38.4% when available iron was reduced.”
“Iron restriction likely impedes heme synthesis upstream of uroporphyrinogen III synthase via decreasing 5-aminolevulinate synthase 2 mRNA translation. Because the tricarboxylic acid cycle enzyme aconitase contains a 4Fe-4S cluster, it also is possible that decreased availability of succinyl coenzyme A, a key substrate for the rate-limiting step in heme production, may play a role,” the researchers wrote.
