Prophylactic heme arginate therapy in acute intermittent hepatic porphyria - a case report

Introduction. Among the acute hepatic porphyrias, a small percentage of
 patients, predominantly female, present with recurrent cyclic attacks of
 acute intermittent porphyria (AIP) that occurs more than three times a year,
 and sometimes at intervals of less than a month. In women, the attacks are
 typically related to menstrual cycle, requiring several days of
 hospitalization and administration of heme arginate. For these patients, the
 prophylactic heme arginate therapy may be the optimal treatment modality.
 Case Report. We present a 40-year-old female patient who has been suffering
 from porphyria for seventeen years. The first attack occurred in 2003,
 presenting with severe neurological symptoms, requiring the use of heme
 arginate Normosang?, which resulted in a favorable therapeutic response. In
 2004 and 2007, gonadorelin analogue Zoladex? (goserelin) was used, but
 without beneficial effects on the course of the disease. In 2008, a
 preventive administration of heme arginate was initiated. The patient
 received heme arginate in the early phase of symptoms, every month in the
 premenstrual phase of the cycle, which resulted in milder symptoms, full
 recovery within 24 hours, lower doses of Normosang? (1-2 ampoules) and fewer
 hospital days (1-2 days) per month. This regimen has significantly improved
 the patient's quality of life and reduced the risk of potential adverse
 effects. Conclusion. Preventive use of Normosang? is the optimal therapeutic
 modality in patients with frequent, recurrent severe attacks that are
 unresponsive to other therapeutic regimens. As a result, patients have a
 better quality of life due to an effective, short-term, targeted treatment
 regimen.


Abstract
Introduction. Among the acute hepatic porphyrias, a small percentage of patients, predominantly female, present with recurrent cyclic attacks of acute intermittent porphyria (AIP) that occurs more than three times a year, and sometimes at intervals of less than a month. In women, the attacks are typically related to menstrual cycle, requiring several days of hospitalization and administration of heme arginate. For these patients, the prophylactic heme arginate therapy may be the optimal treatment modality. Case Report.
We present a 40-year-old female patient who has been suffering from porphyria for seventeen years. The first attack occurred in 2003, presenting with severe neurological symptoms, requiring the use of heme arginate Normosang ® , which resulted in a favorable therapeutic response. In 2004 and 2007, gonadorelin analogue Zoladex ® (goserelin) was used, but without beneficial effects on the course of the disease. In 2008, a preventive administration of heme arginate was initiated. The patient received heme arginate in the early phase of symptoms, every month in the premenstrual phase of the cycle, which resulted in milder symptoms, full recovery within 24 hours, lower doses of Normosang ® (1-2 ampoules) and fewer hospital days (1-2 days) per month. This regimen has significantly improved the patient's quality of life and reduced the risk of potential adverse effects. Conclusion. Preventive use of Normosang ® is the optimal therapeutic modality in patients with frequent, recurrent severe attacks that are unresponsive to other therapeutic regimens. As a result, patients have a better quality of life due to an effective, short-term, targeted treatment regimen. Lek je davan u ranoj fazi simptoma, svakog meseca u premenstrualnoj fazi ciklusa, što je rezultiralo blažim simptomima bolesti, punim oporavkom u toku 24 časa, manjim dozama Normosang-a (1-2 ampule) i manjim brojem hospitalnih dana (1-2 dana) mesečno. Ovim režimom je značajno poboljšan kvalitet života pacijentkinje i smanjen rizik od eventualnih neželjenih efekata leka. Zaključak. Preventivno davanje hem arginata je optimalan terapijski modalitet kod pacijenata sa čestim, rekurentnim, teškim napadima koji ne reaguju na druge terapijske mere. Kao rezultat, pacijenti imaju bolji kvalitet života zahvaljujući kratkom, ciljanom terapijskom režimu.

Introduction
One of the precipitating factors of an attack in acute intermittent hepatic porphyria may be physiological oscillation of female sex hormones during the premenstrual or luteal phase of the menstrual cycle 1 . A small percentage of women have cyclical acute attacks occurring every month, on average a few days before the menstruation 2, 3, 4 . These are commonly severe forms of attacks that may be life-threatening and require hospitalization, intensive monitoring and intravenous heme arginate therapy (Normosang ® ). In such patients, preventive administration of heme arginate may be the optimal therapeutic modality 5, 6 .

Case Report
We present a 40-year-old female patient who has been suffering from acute intermittent hepatic porphyria since 2003. The disease initially presented with a severe acute seizure and neurological symptoms (grand mal epileptic seizures, status epilepticus and coma). The patient's positive family history (mother had porphyria) indicated a qualitative urine test for porphobilinogen (Watson-Schwartz) and it was positive. Urinary porphyrin test was also done, showing elevated levels (15-25 times) of delta aminolevulinic acid, coproporphyrin, uroporphyrin and porphobilinogen (Table 1).
Genetic testing of HMBS and PEPT2 genes is unavailable in Serbia. It can be done only abroad and it is extremely expensive; for that reason, and given the clear clinical picture, it has not been done.
The patient was treated in the intensive care unit, with all supportive measures, and a specific treatment with intravenous heme arginate (Normosang®) was initiated, which resulted in a favorable therapeutic response and complete recovery. After discharge, the patient had recurrent attacks in the premenstrual phase of the cycle, including myalgia and abdominal After five years of heme arginate treatment, a preventive application of the drug was initiated in 2008, every month in the premenstrual phase of the cycle and in the early phase of symptoms. This therapeutic regimen resulted in milder symptoms, lower urinary porphyrin levels ( Table 2 and Table   3), full recovery within 24 hours, and lower doses of Normosang ® (1-2 ampoules). The patient received a dose of 250 mg of heme arginate according to the manufacturer's instructions, through a Port-A-Cath system implanted in the jugular vein. Heme arginate was not given with albumin, nor was the heme/albumin molar ratio calculated. There were no complications such as phlebosclerosis or thrombophlebitis. This therapeutic response allowed a hospital stay of 1-day, with a lower dose of the drug. In this way, the patient's quality of life was significantly improved in the last ten years and reduced the risk of potential adverse effects.
All parameters of potential drug toxicity are documented and presented in annual reports to the manufacturer (Orphan Europe) (Table 4 and Table 5; for 2017), without complications related to the application of the drug, such as thrombophlebitis and phlebosclerosis.
The preventive regimen has proven to be more effective in several aspects. In the first five-year period of preventive use of heme arginate ( (Figure 1).

Discussion
The paper presents a case of a patient with cyclical attacks of acute intermittent hepatic porphyria associated with the menstrual cycle. This phenomenon affects a small number of cases, so there is a lack of literature on the long-term treatment of such patients.
Inducing amenorrhea in order to prevent seizures is one of the therapeutic modalities that may be applied 4,7,8 . In the case of our patient, this therapy did not give favorable results in preventing seizures. In patients with cyclic forms of the disease, who require intravenous administration of heme arginate during the attacks, there is a possibility of applying a preventive heme arginate regimen, immediately before the expected period of discomfort 2-4 , which can give satisfactory therapeutic results in terms of reducing the intensity of attacks, shortening the hospital stay, and decreasing the total dose of heme arginate 9 . This regimen significantly reduces the risks of adverse drug reactions.

Conclusion
The presented case leads to the conclusion that preventive heme arginate therapy may be the optimal therapeutic modality in cases of cyclic attacks of acute intermittent porphyria precipitated by physiological hormonal oscillations during the premenstrual phase of the cycle, as well as in case of negative therapeutic response to other treatments.
This therapeutic approach significantly reduces the intensity of seizures and improves the quality of life of patients due to shorter hospital stay and reduced risk of potential side effects of the drug.