High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria.

BACKGROUND/AIMS: Previous studies have indicated a high risk of hepatocellular carcinoma in acute hepatic porphyrias. In this retrospective study we present the incidence of primary liver cancer and clinical characteristics in a cohort of 179 acute porphyria patients above the age of 50 years. METHODS: Twenty-three cases with primary liver cancer were found either by a surveillance program or due to clinical suspicion. Standardized rate ratio was used to estimate the relative risk of primary liver cancer after indirect standardization. Survival data were calculated using the Kaplan-Meier method. RESULTS: The mean age at diagnosis was 69 years. Hepatocellular carcinoma was found in 19 patients while four patients had cholangiocarcinoma or a combination of the two. Four patients had underlying cirrhosis. Mean tumour size was 4.3 cm in the surveillance group and 10.3 cm in the non-surveillance group (p = 0.01). The overall relative risk of primary liver cancer was 86 above the age of 50: 150 for women and 37 for men. Mean survival time was 5.7 years. CONCLUSION: Acute hepatic porphyria carries a high risk of primary liver cancer above the age of 50 which warrants ultrasound surveillance. Sex distribution and frequency of cirrhosis differs from more common aetiologies of primary liver cancer.

Safety, pharmacokinetics and pharmocodynamics of recombinant human porphobilinogen deaminase in healthy subjects and asymptomatic carriers of the acute intermittent porphyria gene who have increased porphyrin precursor excretion.

BACKGROUND AND OBJECTIVE: Acute intermittent porphyria is an autosomal dominant disorder caused by deficient activity of the third enzyme in the haem biosynthetic pathway, porphobilinogen deaminase. It is characterised by acute, potentially life-threatening neurological attacks that are precipitated by various drugs, reproductive hormones and other factors. During acute attacks, the porphyrin precursors 5-aminolevulinic acid and porphobilinogen accumulate and are excreted at high concentrations in the urine. Current treatment is based on glucose loading and parenteral haem replenishment, which reduce the accumulation of 5-aminolevulinic acid and porphobilinogen. Recently, a new form of treatment based on porphobilinogen deaminase enzyme replacement therapy has been shown to be effective in an acute intermittent porphyria mouse model which, during phenobarbital (phenobarbitone) induction of haem biosynthesis, mimics the biochemical pattern of acute porphyric attacks. The objective of the present study was to investigate the safety, pharmacokinetics and pharmacodynamics of recombinant human porphobilinogen deaminase (P 9808), administered to healthy subjects and asymptomatic porphobilinogen deaminase-deficient subjects with high concentrations of porphobilinogen, the substrate of porphobilinogen deaminase. STUDY DESIGN: Forty individuals participated in this two-part study: 20 asymptomatic porphobilinogen deaminase-deficient subjects (both male and female) with > or =4 times the upper reference urinary porphobilinogen level, and 20 healthy male subjects. Four different doses of recombinant human porphobilinogen deaminase were studied (0.5, 1, 2 and 4 mg/kg bodyweight). Part A included 12 asymptomatic porphobilinogen deaminase-deficient subjects, and the enzyme was administered in an open-label, single-dose design. Part B included 20 asymptomatic porphobilinogen deaminase-deficient subjects and 20 healthy subjects. The same enzyme dosages were administered as divided doses every 12 hours for 4 consecutive days in a randomised, double-blinded, placebo-controlled design. The washout period between Parts A and B was 2 weeks. METHODS: The concentrations of recombinant human porphobilinogen deaminase and titres of antibodies against recombinant human porphobilinogen deaminase were analysed by ELISA. Plasma porphobilinogen and 5-aminolevulinic acid concentrations were analysed using a novel liquid chromatography-tandem mass spectrometry method. Urinary porphobilinogen, 5-aminolevulinic acid and porphyrin concentrations, as well as plasma porphyrin concentrations, were analysed using standard methods. The pharmacodynamic effect of the enzyme was studied through changes in plasma porphobilinogen concentrations. RESULTS: No serious adverse events were observed. Seven subjects (four healthy men and three asymptomatic porphobilinogen deaminase-deficient subjects) developed antibodies against recombinant human porphobilinogen deaminase but did not experience allergic manifestations. The mean elimination half-lives of the highest doses of recombinant human porphobilinogen deaminase ranged between 1.7 and 2.5 hours for both healthy men and asymptomatic porphobilinogen deaminase-deficient subjects. The area under the plasma concentration-time curve was proportional to the respective dose. In asymptomatic porphobilinogen deaminase-deficient subjects, plasma porphobilinogen concentrations decreased below measurable levels almost instantaneously after administration of any dose of the enzyme. The effect lasted for approximately 2 hours, after which the plasma porphobilinogen concentration slowly increased, reaching about 70% of the initial values 12 hours after administration. There was no effect on plasma 5-aminolevulinic acid concentrations, and there was a transitory increment in porphyrin concentrations. The corresponding concentrations of metabolites in the urine reflected the pattern observed in the plasma. CONCLUSIONS: The recombinant human porphobilinogen deaminase enzyme preparation was found to be safe to administer and effective for removal of the accumulated metabolite porphobilinogen from plasma and urine. The pharmacokinetic profile of recombinant human porphobilinogen deaminase showed dose proportionality, and the elimination half-life was about 2.0 hours for the two highest doses. Thus, clinical grounds were established for investigation of the therapeutic efficacy of the enzyme during periods of overt disease in patients with acute intermittent porphyria.

Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks.

BACKGROUND: Acute intermittent porphyria (AIP) is a metabolic disease affecting hepatic heme biosynthesis. The clinical course in overt disease is characterized by acute attacks of neurovisceral symptoms. Treatment is based on symptomatic relief together with carbohydrate loading and in more severe attacks heme therapy. During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine. These metabolites represent the acute phase reactants confirming an ongoing attack and are used to evaluate therapeutic measures. The aim of this study was to measure PBG and ALA in plasma and urine during an acute attack and to match the biochemical pattern with the clinical and therapeutical course. METHODS: Three consecutive AIP patients were included during four acute attacks. Plasma PBG and ALA were measured by a LC-MS method and in urine by ion-exchange chromatography. The patients received symptomatic and glucose treatment at admission to hospital, and four days later, if necessary, heme therapy. RESULTS: In the three attacks that required heme therapy, plasma PBG concentrations had further increased after admission (p=0.01). In the patient that did not require heme therapy, plasma PBG had decreased after admission. CONCLUSIONS: Biochemical monitoring of an acute attack was more accurately reflected by plasma PBG than plasma ALA or urinary PBG and ALA. Glucose administration, in contrast to heme therapy, was not sufficient to achieve clinical and biochemical remission in the more serious attacks.

Variations in porphobilinogen and 5-aminolevulinic acid concentrations in plasma and urine from asymptomatic carriers of the acute intermittent porphyria gene with increased porphyrin precursor excretion.

BACKGROUND: The heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) accumulate during overt crises of acute intermittent porphyria (AIP), and high excretion of these metabolites often continues in the asymptomatic phase. METHODS: We measured concentrations of PBG and ALA and investigated the correlation between these metabolites in plasma and urine in 10 asymptomatic AIP carriers with high excretion and in 5 healthy individuals. We quantified plasma concentrations with an HPLC-mass spectrometric method and urine concentrations with ion-exchange chromatography. RESULTS: The mean (SD) plasma concentrations of PBG and ALA in the AIP carriers were 3.1 (1.0) and 1.7 (0.7) micromol/L, respectively. The mean 8-h urinary excretion amounts of PBG and ALA in the AIP carriers were 102 (25) and 56 (18) micromol, respectively, whereas the corresponding values for healthy individuals were 2.9 (0.7) and 9.3 (1.2) micromol. The correlations between PBG and ALA values in plasma and urine of the AIP carriers were 0.678 and 0.856, respectively. The mean PBG/ALA ratio was approximately 2.0 in both plasma and urine for the AIP carriers and 0.3 in urine for the healthy individuals. The renal clearance rates for PBG and ALA were 71 (15) and 70 (13) mL/min, respectively. CONCLUSIONS: The described HPLC-mass spectrometric method enabled characterization of variations in plasma PBG and ALA in AIP carriers during an 8-h period. The renal clearances were similar for both metabolites. This method could be used to monitor AIP patients during treatment.