EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

Syndrome of inappropriate antidiuretic hormone secretion associated with coproporphyria: case report and review of literature.

OBJECTIVE: To remind physicians to consider the hepatic porphyrias in the differential diagnosis of the syndrome of inappropriate antidiuretic hormone secretion. METHODS: We present a case report of a patient seen in the hospital for severe hyponatremia, who was discovered to have the syndrome of inappropriate antidiuretic hormone secretion attributable to coproporphyria. Results of laboratory tests of the patient and her family are presented. RESULTS: A 54-year-old woman was seen in the hospital because of severe hyponatremia accompanied by generalized seizures. Her serum sodium concentration was 112 mEq/L, with concomitant serum and urine osmolalities of 235 and 639 mOsm/kg, respectively. Renal, thyroid, and adrenal functions were normal. Brain, chest, abdominal, and pelvic imaging studies were negative for occult malignant disease. Urinary excretions of porphobilinogen and aminolevulinic acid were substantially elevated. Results of follow-up urine, plasma, and fecal porphyrin studies were consistent with coproporphyria. Results of porphyrin metabolic studies of the patient's family showed normal findings in her parents and a minimally increased fecal coproporphyrin concentration and urinary uroporphyrin excretion in her sister. CONCLUSION: An endocrinology consultation is often requested for patients with hyponatremia. It is important to consider the acute hepatic porphyrias in the differential diagnosis, even though these are rare disorders and the family history may not always be helpful because of the high frequency of asymptomatic carriers.

Biochemical differentiation of the porphyrias.

OBJECTIVES: To differentiate the porphyrias by clinical and biochemical methods. DESIGN AND METHODS: We describe levels of blood, urine, and fecal porphyrins and their precursors in the porphyrias and present an algorithm for their biochemical differentiation. Diagnoses were established using clinical and biochemical data. Porphyrin analyses were performed by high performance liquid chromatography. RESULTS AND CONCLUSIONS: Plasma and urine porphyrin patterns were useful for diagnosis of porphyria cutanea tarda, but not the acute porphyrias. Erythropoietic protoporphyria was confirmed by erythrocyte protoporphyrin assay and erythrocyte fluorescence. Acute intermittent porphyria was diagnosed by increases in urine delta-aminolevulinic acid and porphobilinogen and confirmed by reduced erythrocyte porphobilinogen deaminase activity and normal or near-normal stool porphyrins. Variegate porphyria and hereditary coproporphyria were diagnosed by their characteristic stool porphyrin patterns. This appears to be the most convenient diagnostic approach until molecular abnormalities become more extensively defined and more widely available.

Multiple chemical sensitivity syndrome and porphyria. A note of caution and concern.

Growing numbers of patients suffering from many symptoms believe that they have a condition called multiple chemical sensitivity syndrome (MCSS). It has been suggested that this syndrome can be triggered by exposure to any of a large and usually incompletely defined number of natural and synthetic chemical substances. Major medical organizations, including the National Research Council and the American Medical Association, have not recognized MCSS as a clinical syndrome because of a lack of valid, well-controlled studies defining it and establishing pathogenesis or origin. Lately, some have proposed that many patients with MCSS suffer from hereditary coproporphyria. However, this purported association is based chiefly on results from a single reference laboratory of a fundamentally flawed assay for erythrocyte coproporphyrinogen oxidase. Although patients with MCSS may, at times, have modest increases in urinary coproporphyrin excretion, this is a common finding found in many asymptomatic subjects or patients with diverse other conditions (eg, diabetes mellitus, heavy alcohol use, liver disease, and many kinds of anemia). Such secondary coproporphyrinuria does not indicate the existence of coproporphyria. To our knowledge, there is no scientifically valid evidence to support an association between MCSS and coproporphyria, nor is there any unifying hypothesis for rationally linking these 2 disorders.

Drug treatment in acute porphyria.

The acute hepatic porphyrias are rare pharmacogenetic diseases inherited as autosomal dominant conditions of low penetrance. The genetic defect is a 50% deficiency of an enzyme of the haem biosynthetic pathway. Patients may develop 'neurovisceral attacks' which include severe abdominal pain, neuropsychiatric manifestations and potentially fatal respiratory paralysis. Attacks occur generally after puberty, are much commoner in females and may be precipitated by endogenous hormonal changes, dieting, alcohol, severe infections, and many drugs. Treatment includes analgesia, early administration of haem, and general supportive measures. Patients are at greater risk of a severe attack on first presentation since an abdominal emergency may be simulated and inappropriate medication, including that for general anaesthesia may exacerbate the crisis. The urine should be tested for raised porphobilinogen, which is pathognomonic of the acute attack, if there is the slightest doubt about diagnosis. The genotype of blood relatives of index cases must be determined so that carriers may avoid drug and other precipitants. Some drugs have been established as safe or unsafe by clinical use, but information about many drugs is not available or is based only on their properties in rodents or in tissue culture systems. The relevance of these to the human condition remains controversial, but drugs shown to be porphyrinogenic in animal systems should be avoided if there is a known safe alternative. Where it is essential to use a drug not known to be safe, close biochemical and clinical observation may warn of an impending attack.

Dual porphyria of coexisting variegata and cutanea tarda.

While porphyria cutanea tarda and porphyria variegata are independent diseases, we report on seven rare cases with a coincidence of these two different porphyrias in one individuum. The mutual clinical symptom was a cutaneous photosensitivity, which is a major symptom in porphyria cutanea tarda and a facultative one in porphyria variegata. Additionally, five patients had also experienced episodes of acute abdominal pain, which were in three cases accompanied by neurological symptoms, thus offering evidence for an acute hepatic porphyria, such as porphyria variegata. Determination of urinary porphyrin metabolites revealed a porphyria cutanea tarda-like excretion pattern with an elevation of uroporphyrin (mean 1134 nmol/24 h, range 563-4052, normal < or = 30) and heptacarboxyporphyrin (mean 389 nmol/24 h, range 64-830, normal < or = 4). In all patients, however, urinary coproporphyrin was also increased, reaching levels too high for porphyria cutanea tarda but typical for porphyria variegata (mean 1788 nmol/24 h, range 142-4168, normal < or = 120). Fecal porphyrin excretion also resembled the variegate-type with a high concentration especially of protoporphyrin (mean 628 nmol/g dry weight, range 401-1018, normal < or = 151), accompanied by an increase of coproporphyrin (mean 194 nmol/g dry weight, range 75-409, normal < or = 37). The urinary porphyrin precursors 5-aminolaevulinic acid and porphobilinogen were markedly elevated only in one patient, who was in an acute porphyric phase at the time of investigation. The activity of uroporphyrinogen decarboxylase in erythrocytes was considerably decreased in six of our cases (33-64%) and slightly diminished in the other one (83% of normal activity).(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between uroporphyrin excretion, acute attacks of hereditary coproporphyria and successful treatment with haem arginate.

1. The increased urinary excretion of porphyrins as well as of their precursors was studied in a patient with hereditary coproporphyria during two acute attacks in which symptoms differed markedly in character and severity. 2. The increase in urinary coproporphyrin was similar in the 'mild' and in the 'severe' attack, indicating a lack of correlation between coproporphyrin level and clinical symptoms. 3. Aminolaevulinic acid, porphobilinogen and uroporphyrin exhibited significantly higher values during the 'severe' attack than during the 'mild' attack. During the severe attack these three compounds were increased 18-, 14- and 46-fold, respectively, compared with increases of 3-, 3- and 8-fold, respectively, during the mild attack. 4. The striking rise in the formation of uroporphyrin was reflected in the plasma porphyrin profile, which revealed predominance of uroporphyrin. In accordance with this finding, an increase in erythrocyte porphobilinogen deaminase of 130% was recorded. 5. The fluorescence emission spectra of saline-diluted plasma (excitation of 405 nm) showed a distinct peak at 618 nm during the 'severe' episode and a small peak during the 'mild' attack, pointing to the possibility of diagnosing an attack simply by following the fluorometric screen of plasma. 6. The 'severe' attack of coproporphyria was treated with daily infusions of haem arginate, 3 mg/kg, every day for 4 days, at the end of which period a dramatic clinical response was observed. The relief of symptoms was found to be clearly related to the moderate decrease in uroporphyrin excretion observed rather than to the steep decline in the precursors.

Safety of general anaesthesia and surgery in acute hepatic porphyria.

Patients with acute hepatic porphyria are denied essential operations because of concern that general anaesthesia and surgery will precipitate a life threatening porphyric crisis. This study assessed the safety of surgery under general anaesthesia in these patients. A combined prospective and retrospective case note study, with a biochemical study, was conducted in 25 patients with acute hepatic porphyria undergoing 38 surgical operations. Clinical outcome measures were survival and occurrence of porphyric crisis after surgery. The biochemical activity of porphyria was assessed by measurement of the perioperative 24 hour excretion of the haem precursors delta amino-laevulinic acid (ALA) and porphobilinogen (PBG). There were no deaths or crises after 29 operations in 19 patients who were known to have porphyria before their surgery, and therefore given only appropriate drugs. These operations include such major procedures as mitral valve replacement, hip replacement, coronary artery grafting, cholecystectomies, and renal transplantation. In eight of these patients the urinary excretion of ALA and PBG were studied, and showed no sustained postoperative increase. Nine operations were performed in eight patients before the diagnosis of porphyria was known and who thus received routine anaesthetic agents. Seven of these patients developed a postoperative porphyric crisis. Two of them died. It is concluded therefore that even the most major surgery can be undertaken safely in patients with porphyria. The risk is for undiagnosed cases.

Acute hereditary coproporphyria induced by the androgenic/anabolic steroid methandrostenolone (Dianabol).

Acute attacks of porphyria can be induced by certain drugs. We report a case of acute coproporphyria induced by methandrostenolone. This is the first report of acute porphyria induced by an androgenic, anabolic steroid.