Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium.

The 108 patients in this report had histories of consistent clinical features such as acute attacks of abdominal, back and/or limb pain or a relative with proven acute porphyria. Biochemical criteria for acute intermittent porphyria included a substantial increase in urinary PBG [>8 mg PBG /24 hours or > 8 mg PBG / g of creatinine, or >2 fold increase (relative to upper limit of normal (ULN) of 4 mg/24 h or mg/g creatinine)] or serum PBG [>0.2 ug/dL, or >2 fold increase (relative to ULN of 0.1 ug/dL)], with little or no increase in plasma or fecal porphyrins or with decreased activity of hydroxymethyl-bilane synthase [HMBS] in erythrocytes. Biochemical criteria for HEREDITARY COPROPORPHYRIA were a substantial increase in PBG an increase in urinary porphyrins [>450 nmol or >300 ug/24 h or /g of creatinine, or more than 1.5-fold increase (relative to ULN of 300 nmol or 200 ug/24 hours or /g of creatinine], normal or only slight increases in plasma porphyrins and a substantial increase in total fecal porphyrins, with a predominance of coproporphyrin III [>400 ug/g dry weight or >2-fold increase (relative to ULN of 200 ug/g dry weight, with a predominance of coproporphyrin III and a coproporphyin III/I ratio >1.5]. Biochemical criteria for VARIEGATE PORPHYRIA were a substantial increase in urinary or serum PBG and/or in urinary coproporphyrin III increases in plasma porphyrins [>2.7 ug/dL, or >3-fold increase (relative to ULN of 0.9 ug/dL)] and a fluorescence emission peak at 626–628 nm or fecal porphyrins [>400 ug/g dry weight or >2-fold increase (relative to ULN of 200 ug/d dry weight, with a predominance of coproporphyrin III and protoporphyrin]. Detailed mutational analyses were carried out on DNA from 105 subjects, and confirmatory disease-causing HMBS, CPOX or PPOX mutations were found in all but 3 cases [2 with ACUTE INTERMITTENT PORPHYRIA and 1 with HEREDITARY COPROPORPHYRIA]. Demographic, clinical, biochemical and genetic data were entered into a central database [maintained at Univ of South Florida], and descriptive statistics were generated. Bivariate analyses were performed using chi-square tests and non-parametric Wilcoxon rank sum tests. Indirect standardization methods were used to compare chronic medical conditions in subjects with acute intermittent porphyria with data from the NHANES 2009–2010 dataset or the United HealthCare database, 2009–2010. All analyses were performed using SAS software, v9.3.

Subjects were mainly female. A substantial majority were non-Hispanic Caucasians. Among those with acute intermittent porphyria, three were American Indian and two were of East Indian or Asian ancestry. One subject with hereditary coproporphyria was East Asian. Among subjects with acute intermittent porphyria, 81% reported onset of symptoms in the 2 nd to 4 th decades of life, with median age at diagnosis of 33 y. Similarly, in hereditary coproporphyria 7/9 and in variegate porphyria 9/9 reported onset of symptoms between 2 nd and 4 th decades [ Table 1 ]. Among subjects with acute intermittent porphyria, 85% reported symptoms attributed to the disease. Symptoms were intermittent but frequent in 54%, occurred only during acute attacks in 28%, and nearly constant in 18%. In hereditary coproporphyria and variegate porphyria, 7/9 and 9/9, respectively, reported symptoms attributed to their disease. Among subjects with cute intermittent porphyria, 48% reported parents with known disease. In coproporphyria and variegate porphyria, 5/9 and 3/9, respectively, reported having parents with porphyria [ Table 1 ]. 37% of subjects with acute intermittent porphyria reported ingestion of medications as triggers for acute attacks; 22% reported weight loss diets as triggers; 16% surgery; and 7% environmental toxins as other precipitating factors. Among the subjects who reported their histories of prior hospitalizations, 55% reported being hospitalized 1–5 times in their life times for acute attacks, whereas 15% reported no hospitalizations for porphyria.. Abdominal pain (74%), nausea/vomiting (73%), weakness (63%), and constipation (60%) were the most commonly reported symptoms during acute attacks. [ Figure 1A ]. Peripheral neuropathy (43%), systemic arterial hypertension (43%) and chronic kidney disease (29%) were the most common chronic medical conditions reported in subjects with acute intermittent porphyria. Two subjects, both without a history of viral hepatitis or excess alcohol use, aged 46 and 49 years, had cirrhosis. A 78 year old woman without cirrhosis had a history of hepatocellular carcinoma that had been resected ten years prior to her enrollment with no evidence of recurrence. She since has recurrent primary carcinoma of the lung. Of additional interest, her brother also had acute intermittent porphyria and died at 78 years due to hepatocellular carcinoma. The Hmbs mutation in this kindred is R167Q. Among subjects with acute intermittent porphyria, 13% reported having undergone appendectomies, 15% reported cholecystectomies, and 16% hysterectomies. 5/9 subjects with coproporphyria and 5/9 with variegate porphyria reported having undergone abdominal surgeries Among subjects with acute intermittent porphyria, 55% reported having received intravenous heme in the form of hematin [Panhematin], during acute attacks. 74% of them assessed hematin as very effective in improving abdominal pain and other manifestations. 50% of these patients reported treatment with opiates during acute attacks, and only 44% of them reported that they were effective. Sixty percent reported pursuing healthy life styles (physical exercise, adequate rest and sleep, efforts to minimize physical or psychological stress, avoidance of alcohol and certain medications). Twenty six percent reported receiving repeated hematin infusions, and 15% reported receiving glucose infusions for prevention. Thirty percent reported taking pain medications every day. By a substantial margin, hematin infusions were felt to be the most effective means of preventing acute attacks. Among various methods for preventing acute attacks, hematin infusions were reported by patients to be most effective with a mean effectiveness of 7.9 [on a scale of 0 (least effective) – 10 (highly effective)]. Glucose infusions, high carbohydrate diets and pain medications scored 4.4, 4.7 and 4.2, respectively [p = 0.0781, 0.0021, and 0.0049, compared to hematin infusions]. Among 18 subjects with other forms of acute porphyria, 2 reported having received repeated hematin infusions for prevention of recurrent attacks, and both reported that they had been very effective. In women with acute intermittent porphyria, 30/63 reported severe pre-menstrual symptoms, 10/58 reported having experienced acute attacks during pregnancy (among whom 2 reported having received hematin for acute attacks during pregnancy), and 14/33 reported worsening symptoms after they had started oral contraceptive pills. Fifty-nine of 60 women with acute intermittent porphyria who had been pregnant carried pregnancies to term with delivery of living, normal newborns, including the two who had had received hematin while pregnant. Among subjects with acute intermittent porphyria, 63% had levels of urinary ALA that were increased with a mean value of 14.6 mg/ g creatinine [range 1.1–60.9]. 74% had levels of urinary PBG that were increased with a mean value of 48.9 mg/ g creatinine [range 0–473]. 5/9 had values of urinary porphyrins that were increased with a mean value of 1305 ug/g creatinine [range 77.4–6334]. The mean RBC HMBS activity was 17 nmol uroporphyrin /mL RBC/h [reference range 20–50]. Mean plasma and fecal porphyrins were within the reference ranges in all. Table 3 provides additional detail on subjects who were documented to have experienced acute attacks of porphyria. Nearly all were relatively young women who often had markedly increased urinary excretions of PBG. They were not obese. All who reported having received Panhematin infusions for management reported prompt and excellent clinical responses, and some also reported good responses to ongoing prophylactic hematin. Among the five subjects with hereditary coproporphyria with available lab data, none had values of urinary ALA, PBG, or porphyrins, nor plasma porphyrin levels that were increased above upper limits of normal. Among the 9 subjects with variegate porphyria, 1/7 had urinary ALA that was slightly increased [7.33 mg/g creatinine]. 3/9 had increased urinary PBG. The mean urinary PBG was 8.6 mg/g creatinine [range 1.6–41.3]. We had urinary porphyrin levels for only one subject with variegate porphyria, and it was within the normal range [187 ug/g creatinine]. In this cohort, however, 2/5 had elevated levels of plasma total porphyrins; the mean plasma total porphyrin level was 1.3 ug/dL [reference range 0–0.9]. A fluorescence emission peak in diluted plasma at neutral pH at 626–628 nm, following excitation with light of ~400–410 nm [the Soret band], was observed in 1 of 3 of our subjects with variegate porphyria in whom these results were available. 2 , 12 – 14 In subjects with acute intermittent porphyria, mutations in the Hmbs gene were identified in 85/87; missense mutations were identified in 45, small insertions/deletions in 15, non-sense mutations in 8 and intronic mutations in 17. 27/85 were novel mutations. The most common missense mutation was R173W. [Despite repeated attempts, samples for genetic testing could not be obtained from two subjects; DNA analysis for one subject is pending.] In subjects with hereditary coproporphyria, mutations in the coproporphyrinogen oxidase gene were identified in 8/9 subjects: missense mutations in 4, small insertions/deletions in 2, and non-sense mutations in 2. Seven of the eight were novel mutations [not found in the Human Gene Mutation Database [Univ of Cardiff, Wales]. Among subjects with variegate porphyria, mutations in the protoporphyrinogen oxidase gene were identified in 9/9 subjects: known missense mutations in 3 and nonsense mutations in 4. 2/9 were novel mutations. We found no statistically significant associations of mutations and symptoms, signs or biochemical abnormalities ( Table 4 ). Additional details regarding the novel mutations and their functional significance will be published elsewhere [Desnick et al, in preparation].

We report the largest group of subjects with well-documented and -characterized acute porphyrias thus far assembled in North America. Our emphasis is on acute intermittent porphyria, which is the most common and severe form of acute porphyria in the USA. Among the important features are the following: 1. There is a substantial preponderance of females [83%] over males. 2. Fewer than half the subjects reported a parent with known acute porphyria, confirming the variable expression of the clinical phenotype, even within individual kindreds. 3. The onset of symptoms usually occurs during second through fourth decades of life [81%]. 4. Medications [37%] and weight loss diets [22%] are the most commonly reported triggers of acute attacks. 5. 18% feel they suffer from chronic, ongoing symptoms. There are high prevalences of chronic medical conditions such as peripheral neuropathy [43%], systemic arterial hypertension [43%], chronic kidney disease [29%], and history of abdominal surgeries [appendectomy 13%, and cholecystectomy 15%. The prevalences of systemic arterial hypertension, psychiatric conditions, and seizures are significantly greater than that in the general population, matched for age and gender Cholecystectomies had been performed in a far higher percentage of subjects with acute intermittent porphyria than in a control cohort [15% vs 0.2%, p <0.001] ( Table 2 ). Recent results from a genetic analysis of French blood donors indicate that the frequency of genetic defects in the Hmbs gene in unselected subjects is as high as 1/1675 [59/100,000], which is much higher than previous estimates [~5/100,000]. 20 Fifty five percent of subjects reported having received hematin during acute attacks, and most (74%) felt that hematin was very effective in treatment of acute attacks 26% of subjects received repeated hematin infusions for prevention of acute attacks, and hematin was the most effective treatment for prevention of recurrent attacks. This is consistent with a previous study suggesting that approximately one third of patients treated with hematin in the U.S. receive prophylactic treatment 17 . In addition, 60% reported as beneficial life style modifications, such as avoidance of alcohol and certain medications and increasing physical exercise. Because of the perceived substantial therapeutic benefit from the use of intravenous hematin, such treatment should be widely and easily available to patients with well-established diagnoses of acute porphyria. One of our subjects with acute intermittent porphyria, a 36 year old woman with severe recurrent attacks, underwent orthotopic liver transplantation. The surgery was uneventful and resulted in rapid normalization of plasma and urinary ALA and PBG and to a rapid, complete, and ongoing resolution of symptoms related to acute intermittent porphyria. This case will be reported in detail elsewhere [Liu et al, personal communication]. The biochemical and clinical improvement seen in this subject is in agreement with recently published results of liver transplantation for acute intermittent porphyria 18 . Genetic analyses of the genes known to be affected in acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria detected mutations adequate to account for the occurrence of disease in nearly all subjects. Novel, not previously described mutations in the related genes were detected in 19% of the patients. There were no significant associations among clinical or laboratory abnormalities and the general types of mutations found, nor with specific mutations among those more frequently observed [ Table 4 ]. Disease manifestations were less frequent and severe in hereditary coproporphyria and variegate porphyria than in acute intermittent porphyria. Most subjects [16/18] reported onset of symptoms between 2 nd and 4 th decades of life, but correct diagnosis was delayed by ~15 years. The clinical features were generally similar to those reported by subjects with acute intermittent porphyria. DNA studies were useful for diagnostic confirmation in 15/16 subjects with hereditary coproporphyria and variegate porphyria, including those with normal urinary porphyrins and porphyrin precursors. Strengths of our study include use of a standardized protocol with rigorous biochemical and/or molecular inclusion criteria for diagnosis and the application of state-of-the art biochemical and genetic testing methods. In conclusion, most patients with symptomatic acute porphyrias in the USA are women who first develop symptoms in the 2 nd to 4 th decades of life. The cardinal symptom is severe generalized abdominal pain, often with nausea and vomiting. There are significantly increased frequencies of systemic arterial hypertension, chronic renal and psychiatric disease and seizures. Genetic analyses reveal diverse mutations in the genes underlying these disorders. Patients report that the most effective therapy of acute attacks is intravenous hematin. Thus, 2 , 13 we believe that patients with acute porphyrias and with symptoms severe enough to come to the Emergency Department and/or to be hospitalized, should be treated as expeditiously as possible with intravenous hematin. In addition, prophylactic and repeated administration of intravenous hematin is of benefit to those prone to recurrent attacks, 21 and hematin is safe for use in women who are pregnant. Hematin was the first drug approved under the Orphan Drug Act, and, it should be readily available to all symptomatic patients with well documented acute porphyrias.