AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review.

DESCRIPTION: The acute hepatic porphyrias (AHP) are rare, inborn errors of heme-metabolism and include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and porphyria due to severe deficiency of 5-aminolevulinic acid dehydratase. Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of approximately 1 in 100,000. The major clinical presentation involves attacks of severe pain, usually abdominal and generalized, without peritoneal signs or abnormalities on cross-sectional imaging. Acute attacks occur mainly in women in their childbearing years. AHP should be considered in the evaluation of all patients, and especially women aged 15-50 years with recurrent severe abdominal pain not ascribable to common causes. The screening tests of choice include random urine porphobilinogen and δ-aminolevulinic acid corrected to creatinine. All patients with elevations in urinary porphobilinogen and/or δ-aminolevulinic acid should initially be presumed to have AHP. The cornerstones of management include discontinuation of porphyrinogenic drugs and chemicals, administration of oral or intravenous dextrose and intravenous hemin, and use of analgesics and antiemetics. Diagnosis of AHP type can be confirmed after initial treatment by genetic testing for pathogenic variants in HMBS, CPOX, PPOX, and ALAD genes. AHP is also associated with chronic symptoms and long-term risk of systemic arterial hypertension, chronic renal and liver disease, and hepatocellular carcinoma. Patients who have recurrent acute attacks (4 or more per year) should be considered for prophylactic therapy with intravenous hemin or subcutaneous givosiran. Liver transplantation is curative and reserved for patients with intractable symptoms who have failed other treatment options. METHODS: This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Women aged 15-50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup should be considered for screening for an AHP. BEST PRACTICE ADVICE 2: Initial diagnosis of AHP should be made by biochemical testing measuring δ-aminolevulinic acid, porphobilinogen, and creatinine on a random urine sample. BEST PRACTICE ADVICE 3: Genetic testing should be used to confirm the diagnosis of AHP in patients with positive biochemical testing. BEST PRACTICE ADVICE 4: Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein. BEST PRACTICE ADVICE 5: In addition to intravenous hemin, management of acute attacks of AHP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia, and hypomagnesemia, if present. BEST PRACTICE ADVICE 6: Patients should be counseled to avoid identifiable triggers that may precipitate acute attacks, such as alcohol and porphyrinogenic medications. BEST PRACTICE ADVICE 7: Prophylactic heme therapy or givosiran, administered in an outpatient setting, should be considered in patients with recurrent attacks (4 or more per year). BEST PRACTICE ADVICE 8: Liver transplantation for AHP should be limited to patients with intractable symptoms and significantly decreased quality of life who are refractory to pharmacotherapy. BEST PRACTICE ADVICE 9: Patients with AHP should be monitored annually for liver disease. BEST PRACTICE ADVICE 10: Patients with AHP, regardless of the severity of symptoms, should undergo surveillance for hepatocellular carcinoma, beginning at age 50 years, with liver ultrasound every 6 months. BEST PRACTICE ADVICE 11: Patients with AHP on treatment should undergo surveillance for chronic kidney disease annually with serum creatinine and estimated glomerular filtration rate. BEST PRACTICE ADVICE 12: Patients should be counseled on the chronic and long-term complications of AHP, including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma, and need for long-term monitoring.

In Vitro Effect of Epigallocatechin Gallate on Heme Synthesis Pathway and Protoporphyrin IX Production.

Photodynamic therapy (PDT) treats nonmelanoma skin cancer. PDT kills cells through reactive oxygen species (ROS), generated by interaction among cellular O2, photosensitizer and specific light. Protoporphyrin IX (PpIX) is a photosensitizer produced from methyl aminolevulinate (MAL) by heme group synthesis (HGS) pathway. In PDT-resistant cells, PDT efficacy has been improved by addition of epigallocatechin gallate (EGCG). Therefore, the aim of this work is to evaluate the effect of EGCG properties over MAL-TFD and PpIX production on A-431 cell line. EGCG's role over cell proliferation (flow cytometry and wound healing assay) and clonogenic capability (clonogenic assay) was evaluated in A-431 cell line, while the effect of EGCG over MAL-PDT was determined by cell viability assay (MTT), PpIX and ROS detection (flow cytometry), intracellular iron quantification and gene expression of HGS enzymes (RT-qPCR). Low concentrations of EGCG (<50 µM) did not have an antiproliferative effect over A-431 cells; however, EGCG inhibited clonogenic cell capability. Furthermore, EGCG (<50 µM) improved MAL-PDT cytotoxicity, increasing PpIX and ROS levels, exerting a positive influence on PpIX synthesis, decreasing intracellular iron concentration and modifying HGS enzyme gene expression such as PGB (upregulated) and FECH (downregulated). EGCG inhibits clonogenic capability and modulates PpIX synthesis, enhancing PDT efficacy in resistant cells.

Palliative Care Aspects of Acute Intermittent Porphyria - A Case Report.

Acute intermitttent porphyria belongs to a rare group of diseases hallmarked by deficient biosynthesis of heme. It carries a significant symptom burden, both physical and emotional,and therefore palliative care has emerged as an essential tool in the armamentarium of porphyria management . It takes care of the patient as a whole and caters to all aspects that the disease process demands. There are many lacunae in the literature regarding the palliative management of porphyria. We are reporting a case of a 16-year-old female who presented with severe abdominal pain, lower backache and symmetrical bilateral lower limb pain to the palliative ward referred by the neurology department for supportive care. This case describes the palliative care aspects of porphyria management which was successfully provided in the palliative care unit right from referral till the last. A multidisciplinary palliative care team managed the patient, and the necessary interventions were provided to the patient and family. Palliative acre in AIP needs to be emphasized, and palliative care services need to be utilized in these cases. The unavailability of specific treatment measure, heme, in countries like India further emphasizes the need for long-term supportive care for the patient and family. The case shows the importance of palliative care throughout the disease course as it is a chronic disease with significant morbidity and carries a heavy symptom burden. This case provides the insight that rather than conventional management alone for such chronic diseases, palliative care should be incorportated. Early integration with palliative care helps in exploring all the domains of disease. This is one of the first cases reported highlighting palliative care in porphyria , bridging the gap in the literature.

Acute hepatic porphyrias: Recommendations for diagnosis and management with real-world examples.

Acute hepatic porphyria (AHP) is a group of four rare inherited diseases, each resulting from a deficiency in a distinct enzyme in the heme biosynthetic pathway. Characterized by acute neurovisceral symptoms that may mimic other medical and psychiatric conditions, lack of recognition of the disease often leads to a delay in diagnosis and initiation of effective treatment. Biochemical testing for pathway intermediates that accumulate when the disease is active forms the basis for screening and establishing a diagnosis. Subsequent genetic analysis identifies the pathogenic variant, supporting screening of family members and genetic counseling. Management of AHP involves avoidance of known exogenous and hormonal triggers, symptomatic treatment, and prevention of recurrent attacks. Here we describe six case studies from our own real-world experience to highlight current recommendations and challenges associated with the diagnosis and long-term management of the disease.

Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients.

Acute intermittent porphyria (AIP) is a rare hereditary metabolic disease characterized by acute attacks and accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP have a high risk of primary liver cancer (PLC). We aimed to assess the association between porphyrin precursor excretion and the risk for PLC in patients with AIP. We studied 48 patients with AIP who developed PLC between 1987 and 2015 and 140 age and sex matched controls with AIP but no PLC. Data on all available urinary PBG and ALA samples collected from 1975 until 1 year before PLC diagnosis were analyzed and compared between cases and controls using logistic regression. Porphyrin precursor excretion was higher in patients with PLC (PBG median 7.9 [IQR 4.4-21.9] mmol/mol creatinine) than in controls (3.8 [1.2-9.8]) (adjusted odds ratio 1.07, 95% confidence interval: 1.02-1.12). None of the 28 patients with all registered samples below the upper limit of normal (ULN) developed PLC, and only one of the 45 patients with all samples <2× ULN developed PLC. Among non-PLC controls, ALA and PBG levels decreased after age 50-60 while an increasing trend was observed after age 65 among those who developed PLC. Increased urinary porphyrin precursors are associated with a high risk of developing PLC. Patients with normal levels appear to have a low risk while high or increasing ALA and PBG after age 65 indicates high risk, which should be considered in surveillance decisions.

A randomized, placebo-controlled study of givosiran in patients with acute hepatic porphyrias (ENVISION): Final (36-month) analysis of the Taiwan Cohort.

BACKGROUND/PURPOSE: Acute hepatic porphyrias (AHP) are rare genetic disorders associated with acute neurovisceral attacks and chronic symptoms. This analysis was conducted to examine the long-term efficacy and safety of givosiran in Taiwanese participants in the ENVISION study (NCT03338816). METHODS: Patients (age ≥12 years) with AHP and recurrent attacks were randomized to receive givosiran 2.5 mg/kg or placebo for 6 months during the double-blind period. Patients then switched from placebo to givosiran (placebo crossover group) or continued taking givosiran (continuous givosiran group) during a 30-month open-label extension period. The total study duration was 36 months. An analysis was conducted that included patients enrolled in Taiwan (N = 7). RESULTS: During the double-blind period and open-label extension period, the median annualized attack rates were 0.0 and 0.0, respectively, in the continuous givosiran group (n = 5) and 15.1 and 4.6, respectively, in the placebo crossover group (n = 2; 70 % decrease). Median annualized days of hemin use in the double-blind period and open-label extension period were 0.0 and 0.0, respectively, in the continuous givosiran group, and 23.8 and 5.0, respectively, in the placebo crossover group (79 % decrease). EQ-5D VAS scores remained relatively stable in both groups, and PPEQ responses indicated improved functioning and satisfaction in both groups. Delta-aminolevulinic acid and porphobilinogen levels remained low with long-term givosiran treatment. Serious adverse events were reported by 3 patients (43 %). CONCLUSIONS: Long-term efficacy and safety results in the Taiwan cohort are consistent with those in the global cohort.

Biochemical and molecular characterization of a novel porphobilinogen synthase from Corynebacterium glutamicum.

Corynebacterium glutamicum porphobilinogen synthase (PBGS) is a metal enzyme with a hybrid active site metal binding sequence. In this study, the porphobilinogen synthase gene of C. glutamicum was cloned and heterogeneously expressed in Escherichia coli. C. glutamicum PBGS was purified, and its enzymatic characteristics were analyzed. The results showed that C. glutamicum PBGS is a Zn2+-dependent enzyme, and Mg2+ has allosteric regulation. The allosteric Mg2+ plays a vital role in forming the quaternary structure of C. glutamicum PBGS. Based on the ab initio predictive structure modeling of the enzyme and the molecular docking model of 5-aminolevulinic acid (5-ALA), 11 sites were selected for site-directed mutagenesis. When the hybrid active site metal binding site of C. glutamicum PBGS is converted into a cysteine-rich motif (Zn2+-dependent) or an aspartic acid-rich motif (Mg2+/K+-dependent), the enzyme activity is basically lost. Four residues, D128, C130, D132, and C140, in the metal binding site, were the binding sites of Zn2+ and the active center of the enzyme. The band migration, from the native PAGE, of five variants with mutations in the center of enzyme activity was the same as that of the variant enzymes as purified, individually adding two metal ion chelating agents. Their Zn2+ active center structures were abnormal, and the quaternary structure equilibrium was altered. The destroyed active center affects the construction of its quaternary structure. The quaternary structural balance between octamer and hexamer through dimers was regulated by the allosteric regulation of C. glutamicum PBGS. The enzyme activity was also affected by the change of the active site lid structure and (α ß)8-barrel structure caused by mutation. Structural changes in the variants were analyzed to understand C. glutamicum PBGS better.

RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria.

Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic heme biosynthesis. They are associated with attacks of neurovisceral manifestations that can be life threatening and constitute what is considered an acute porphyria attack. Until recently, the sole specific treatment for acute porphyria attacks consisted of the intravenous administration of hemin. Although attacks are often sporadic, some patients develop recurrent acute attacks, with devastating effects on quality of life. Liver transplantation has historically been the sole curative treatment option. The clinical manifestations of AHP are attributed to the accumulation of the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Advances in molecular engineering have provided new therapeutic possibilities for modifying the heme synthetic pathway. We reviewed the background and current status of AHP treatment using liver-directed small interfering RNA targeting ALAS1. The therapeutic aim was to normalize the levels of ALAS1, which is highly upregulated during acute porphyria attacks. Givosiran is now an approved drug for use in adults and adolescents aged 12 years and older. The results of clinical trials have shown that givosiran treatment leads to a rapid and sustained reduction of ALAS1 mRNA, decreased heme precursor levels, and a decreased rate of acute attacks compared with placebo. The clinical trials (phases I, II, and III) were all randomized and placebo controlled. Many patients enrolled in the initial clinical trials have continued treatment in open label extension and extended/compassionate-use programs in countries where givosiran is not yet commercially available.

Crystal structures of hydroxymethylbilane synthase complexed with a substrate analog: a single substrate-binding site for four consecutive condensation steps.

Hydroxymethylbilane synthase (HMBS), which is involved in the heme biosynthesis pathway, has a dipyrromethane cofactor and combines four porphobilinogen (PBG) molecules to form a linear tetrapyrrole, hydroxymethylbilane. Enzyme kinetic study of human HMBS using a PBG-derivative, 2-iodoporphobilinogen (2-I-PBG), exhibited noncompetitive inhibition with the inhibition constant being 5.4 ± 0.3 µM. To elucidate the reaction mechanism of HMBS in detail, crystal structure analysis of 2-I-PBG-bound holo-HMBS and its reaction intermediate possessing two PBG molecules (ES2), and inhibitor-free ES2 was performed at 2.40, 2.31, and 1.79 Šresolution, respectively. Their overall structures are similar to that of inhibitor-free holo-HMBS, and the differences are limited near the active site. In both 2-I-PBG-bound structures, 2-I-PBG is located near the terminus of the cofactor or the tetrapyrrole chain. The propionate group of 2-I-PBG interacts with the side chain of Arg173, and its acetate group is associated with the side chains of Arg26 and Ser28. Furthermore, the aminomethyl group and pyrrole nitrogen of 2-I-PBG form hydrogen bonds with the side chains of Gln34 and Asp99, respectively. These amino acid residues form a single substrate-binding site, where each of the four PBG molecules covalently binds to the cofactor (or oligopyrrole chain) consecutively, ultimately forming a hexapyrrole chain. Molecular dynamics simulation of the ES2 intermediate suggested that the thermal fluctuation of the lid and cofactor-binding loops causes substrate recruitment and oligopyrrole chain shift needed for consecutive condensation. Finally, the hexapyrrole chain is hydrolyzed self-catalytically to produce hydroxymethylbilane.

[Acute porphyrias viewed differently]. / Akute Porphyrien mal anders betrachtet.

The acute porphyrias are a group of four metabolic defects in which the heme synthesis in the liver is disrupted. They are characterized by massively painful acute attacks, which can be life-threatening if not diagnosed. To raise the awareness for these rare disorders, a heme molecule in cartoon style is introduced, which accurately explains the basic biochemical processes in the body and mediates important information on the acute hepatic porphyrias in a simplified and attractive way. The article is complemented by a case report.

Plasmodium falciparum hydroxymethylbilane synthase does not house any cosynthase activity within the haem biosynthetic pathway.

Uroporphyrinogen III, the universal progenitor of macrocyclic, modified tetrapyrroles, is produced from aminolaevulinic acid (ALA) by a conserved pathway involving three enzymes: porphobilinogen synthase (PBGS), hydroxymethylbilane synthase (HmbS) and uroporphyrinogen III synthase (UroS). The gene encoding uroporphyrinogen III synthase has not yet been identified in Plasmodium falciparum, but it has been suggested that this activity is housed inside a bifunctional hybroxymethylbilane synthase (HmbS). Additionally, an unknown protein encoded by PF3D7_1247600 has also been predicted to possess UroS activity. In this study it is demonstrated that neither of these proteins possess UroS activity and the real UroS remains to be identified. This was demonstrated by the failure of codon-optimized genes to complement a defined Escherichia coli hemD- mutant (SASZ31) deficient in UroS activity. Furthermore, HPLC analysis of the oxidized reaction product from recombinant, purified P. falciparum HmbS showed that only uroporphyrin I could be detected (corresponding to hydroxymethylbilane production). No uroporphyrin III was detected, showing that P. falciparum HmbS does not have UroS activity and can only catalyze the formation of hydroxymethylbilane from porphobilinogen.

Porphyria attacks in prepubertal children and adolescents.

CONTEXT: The clinical and laboratory features of dominant acute hepatic porphyrias (AHPs) in prepubertal children and adolescents have not been well established. OBJECTIVE: To evaluate clinical and laboratory features of AHPs in prepubertal children and adolescents compared to adults. DATA SOURCES: OVID (Embase Classic+Embase and MEDLINE), Scopus, and Google Scholar. STUDY SELECTION: Studies describing symptomatic children or adolescents (<18 years old) with increased urinary porphobilinogen were included. DATA EXTRACTION: Two reviewers independently extracted the data, with a third reviewer arbitrating discrepancies. RESULTS: 100 studies were included describing 112 patients (26 prepubertal children and 86 adolescents). Differences were found between prepubertal children and adolescents regarding sex distribution (female-to-male ratio: 1:2 vs. 4:1), clinical manifestations, and concomitant clinical manifestations. LIMITATIONS: There was variation in the methods used to diagnose porphyria attacks across studies, and some elements of the quality of individual studies were unclear. CONCLUSIONS: Prepubertal children with AHPs and porphyria attacks presented with distinct demographic and clinical characteristics from adolescents and adults. Nearly two-thirds of the affected children were males, and about half had a concomitant medical condition that can constitutively upregulate hepatic δ-aminolevulinic acid synthase-1. Adolescents were comparable to adults in almost all respects.

Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.

Pathogenic heterozygous variants in HMBS encoding the enzyme hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase, cause acute intermittent porphyria (AIP). Biallelic variants in HMBS have been reported in a small number of children with severe progressive neurological disease and in three adult siblings with a more slowly, progressive neurological disease and distinct leukoencephalopathy. We report three further adult individuals who share a distinct pattern of white matter abnormality on brain MRI in association with biallelic variants in HMBS, two individuals with homozygous variants, and one with compound-heterozygous variants. We present their clinical and radiological features and compare these with the three adult siblings previously described with leukoencephalopathy and biallelic HMBS variants. All six affected individuals presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. This recognizable pattern of MRI abnormalities is seen in all six adults described here. Biallelic variants in HMBS cause a phenotype that is distinct from AIP. It is not known whether AIP treatments benefit individuals with HMBS-related leukoencephalopathy. One individual reported here had improved neurological function for 12 months following liver transplantation followed by decline and progression of disease.

Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators.

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the haem biosynthesis pathway. In susceptible HMBS mutation carriers, triggering factors such as hormonal changes and commonly used drugs induce an overproduction and accumulation of toxic haem precursors in the liver. Clinically, this presents as acute attacks characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, and, in the long-term setting, the development of primary liver cancer, hypertension and kidney failure. Treatment options are few, and therapies preventing the development of symptomatic disease and long-term complications are non-existent. Here, we provide an overview of the disorder and treatments already in use in clinical practice, in addition to other therapies under development or in the pipeline. We also introduce the pathomechanistic effects of HMBS mutations, and present and discuss emerging therapeutic options based on HMBS stabilisation and the regulation of proteostasis. These are novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality. The present scenario appears promising for upcoming patient-tailored interventions in AIP.

Activated Carbon Fabric Mask Reduces Lead Absorption and Improves the Heme Biosynthesis and Hematological Parameters of Battery Manufacturing Workers.

Activated carbon fabrics (ACF) mask prevents the absorption of lead and reduce its adverse effects of human health. Aim of this study to know the blood lead level and its effects on heme biosynthesis and hematological parameters after using 2 months activated carbon fabric mask of battery manufacturing workers (BMW). Blood lead level, heme biosynthesis and hematological parameters were measured by using standard method. Blood lead level (P < 0.001, - 13.5%) was significantly decreased, activated δ-aminolevulinic acid dehydratase (P < 0.001, 11.97%) and non-activated δ- aminolevulinic acid dehydratase (P < 0.001, 23.17%) enzyme activity were significantly increased, however, the ratio of activated to Non-activated δ- ALAD (P < 0.001, - 10.13%) was significantly decreased, urinary excretion of δ- aminolevulinic acid (P < 0.001, - 10.49%) and porphobilinogen (P < 0.001, - 7.38%) were significantly decreased after using 2 months ACF mask as compared to before using mask of BMW. Hematological parameters i.e Hb (P < 0.05, 13.42%), PCV (P < 0.05, 7.23%), MCV (P < 0.05, 1.9%) were significantly increased and total WBC count (P < 0.05, - 5.18%) was significantly decreased after using 2 months ACF mask as compared to before using mask of BMW. Two months using ACF mask reduces the blood lead level and improves the δ-ALDH activity and hematological parameters, decreases the urinary excretion of δ-ALA, PBG of battery manufacturing workers. Therefore, the regular using of ACF mask is beneficial to prevent the lead absorption and its adverse effects on human health.

Kidney transplantation improves the clinical outcomes of Acute Intermittent Porphyria.

BACKGROUND: Acute Intermittent Porphyria (AIP) is a rare inherited autosomal dominant disorder of heme biosynthesis. Porphyria-associated kidney disease occurs in more than 50% of the patients with AIP, and end stage renal disease (ESRD) can be a devastating complication for AIP patients. The outcomes of AIP patients after kidney transplantation are poorly known. METHODS: We examined the outcomes of 11 individuals with AIP, identified as kidney transplant recipients in the French Porphyria Center Registry. RESULTS: AIP had been diagnosed on average 19 years before the diagnosis of ESRD except for one patient in whom the diagnosis of AIP had been made 5 years after the initiation of dialysis. Median follow-up after transplantation was 9 years. A patient died 2 months after transplantation from a cardiac arrest and a patient who received a donation after cardiac death experienced a primary non-function. No rejection episode and no noticeable adverse event occurred after transplantation. Serum creatinine was on average 117 µmol/l, and proteinuria <0.5 g/l in all patients at last follow up. All usually prescribed drugs after transplantation are authorized except for trimethoprim/sulfamethoxazole. Critically, acute porphyria attacks almost disappeared after kidney transplantation, and skin lesions resolved in all patients. CONCLUSION: Kidney transplantation is the treatment of choice for AIP patients with ESRD and dramatically reduces the disease activity.

Acute hepatic porphyrias: Current diagnosis & management.

Each of the four acute hepatic porphyrias is due to mutation of an enzyme in the heme biosynthetic pathway. The accumulation of pathway intermediates that occur most notably when these diseases are active is the basis for screening and establishing a biochemical diagnosis of these rare disorders. Measurement of enzyme activities and especially DNA testing also are important for diagnosis. Suspicion of the diagnosis and specific testing, particularly measurement of urinary porphobilinogen, are often delayed because the symptoms are nonspecific, even when severe. Urinary porphyrins are also measured, but their elevation is much less specific. If porphobilinogen is elevated, second line testing will establish the type of acute porphyria. DNA testing identifies the familial mutation and enables screening of family members. Management includes removal of triggering factors whenever possible. Intravenous hemin is the most effective treatment for acute attacks. Carbohydrate loading is sometimes used for mild attacks. Cyclic attacks, if frequent, can be prevented by a GnRH analogue. Frequent noncyclic attacks are sometime preventable by scheduled (e.g. weekly) hemin infusions. Long term complications may include chronic pain, renal impairment and liver cancer. Other treatments, including RNA interference, are under development.

Sex differences in vascular reactivity in mesenteric arteries from a mouse model of acute intermittent porphyria.

BACKGROUND AND AIMS: Acute intermittent porphyria (AIP) results from a partial deficiency of porphobilinogen deaminase (PBGD). Symptomatic AIP patients, most of whom are women, experience acute attacks characterized by severe abdominal pain and abrupt increases in blood pressure. Here, we characterized the reactivity of mesenteric arteries from male and female AIP mice with ~30% of normal PBGD activity and wild type C57BL/6 mice. METHODS: An acute porphyric attack was induced in AIP mice by treatment with phenobarbital. Vascular responses to K+, phenylephrine (PE), acetylcholine (ACh), and hemin were determined (Wire Multi Myograph). RESULTS: Maximal contraction to PE was increased in arteries from male and female AIP mice (p < .05) during an induced attack of acute porphyria. Female AIP arteries had increased sensitivity to PE (p < .05) even after nitric oxide (NO) blockade with Nω-nitro-L-arginine methyl ester (L-NAME) (p < .05). Maximal relaxation to ACh was similar in males and females with lower sensitivity in female AIP arteries (p < .05). Hemin induced greater relaxation in AIP arteries in both males and females (p < .05). SUMMARY/CONCLUSIONS: Sex differences in this AIP mouse model include a pro-contractile response in females. These alterations may contribute to the increased blood pressure during an acute attack and provide a novel mechanism of action whereby heme ameliorates the attacks.

Pilot study of mitochondrial bioenergetics in subjects with acute porphyrias.

BACKGROUND AND AIMS: The acute porphyrias are characterized by defects in heme synthesis, particularly in the liver. In some affected patients, there occurs a critical deficiency in a regulatory heme pool within hepatocytes that leads to up-regulation of 5-aminolevulinic acid [ALA] synthase-1, which is the first and normally rate-controlling enzyme in the pathway. In earlier work, we described defects in mitochondrial functions in cultured skin fibroblasts from patients with acute intermittent porphyria [AIP]. Others described defects in livers of murine models of AIP. Here, we explored mitochondrial energetics in peripheral blood mononuclear cells [PBMCs] and platelets in persons with AIP and hereditary coproporphyria [HCP]. Our hypotheses were that there are deficits in bioenergetic capacity in acute porphyrias and that subjects with more severe acute porphyria have more pronounced reductions in mitochondrial oxygen consumption rates [OCR]. METHODS: We studied 17 subjects with acute hepatic porphyrias, 14 with classical AIP, one with severe AIP due to homozygous deficiency of hydroxymethylbilane synthase [HMBS], 2 with HCP, and 5 non-porphyric controls. We collected peripheral blood, isolated PBMCs, which we assayed either immediately or after frozen storage [80C] for up to 14 days. Using Seahorse XF-24-3, we measured OCR in the presence of glucose + pyruvate under basal condition, and after additions of oligomycin, carbonylcyanide p-trifluoromethoxyphenylhydrazone [FCCP], and antimycin+rotenone. RESULTS: Most subjects [13/17, 76%] were female. Subjects with moderate/severe symptoms associated with acute porphyria had significantly lower basal and maximal-OCR than those with no/mild symptoms who were the same as controls. We observed significant inverse correlation between urinary porphobilinogen [PBG] excretion and OCR. The subject with homozygous AIP had a much lower-OCR than his asymptomatic parents. SUMMARY/CONCLUSIONS: Results support the hypothesis that active acute hepatic porphyria is characterized by a deficiency in mitochondrial function that is detectable in PBMCs, suggesting that limitations in electron transport and ATP production exist in such individuals.

Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs).

The acute hepatic porphyrias include four disorders: acute intermittent porphyria [AIP], hereditary coproporphyria [HCP], variegate porphyria [VP], and the rare porphyria due to severe deficiency of ALA dehydratase [ADP]. In the USA, AIP is the most severe and most often symptomatic. AIP, HCP, and VP are due to autosomal dominant genetic abnormalities, in which missense, nonsense, or other mutations of genes of normal hepatic heme biosynthesis, in concert with other environmental, nutritional, hormonal and genetic factors, may lead to a critical deficiency of heme, the end-product of the pathway, in a small but critical 'regulatory pool' within hepatocytes. This deficiency leads to de-repression of the first and normally rate-controlling enzyme of the heme synthetic pathway, delta- or 5-aminolevulinic acid [ALA] synthase-1, and thus to marked up-regulation of this key enzyme and to marked hepatic overproduction of ALA. In addition, except for ADP, there is marked overproduction as well of porphobilinogen [PBG], the intermediate immediately downstream of ALA in the synthetic chain, and, especially in HCP and VP, also porphyrinogens and porphyrins farther down the pathway. The major clinical features of the acute porphyrias are attacks of severe neuropathic-type pain. Pain is felt first and foremost in the abdomen but may also occur in the back, chest, and extremities. Attacks are more common in women than in men [ratio of about 4:1], often accompanied by nausea, vomiting, constipation, tachycardia, and arterial hypertension. Hyponatremia may also occur. Some patients also describe chronic symptoms of pain, anxiety, insomnia, and others.