Highlights
- •In AP, 5-aminolevulinate-synthase(ALAS1) induction,a vit.B6-dependent enzyme,is present
- •Vit.-B6 is requested by enzymes that catabolize homocysteine(Hcy).
- •Heme itself is an important cofactor for CBS.
- •AP patients show frequently HHcy that may result from vitamin and heme deficiency.
- •HHcy may represent an indirect marker of ALAS1-induction
Abstract
Background
Acute porphyrias (AP) are characterized by heme deficiency and induction of hepatic
5-aminolevulinate synthase (ALAS1). Hyperhomocysteinemia (HHcy) is associated with
endothelial damage, neurotoxicity and increased risk for vascular diseases. Interestingly,
both heme biosynthesis and sulphur amino acid metabolism require vitamin B6, (Pyridoxal-phosphate,
PLP) an important cofactor of ALAS1 and of cystathionine β-synthase (CBS) and cystathionine
γ-lyase (CGL) enzymes that catabolize homocysteine (Hcy). Moreover, heme itself is
an important cofactor for CBS.
Aim
to assess plasma Hcy status and HHcy main determinants in patients with AP.
Materials and methods
A total of 46 patients with AP (31 with Acute Intermittent Porphyria,15 with Variegate
Porphyria) were assessed for clinical status (symptomatic vs. asymptomatic), serum
Hcy, Cysteine (Cys), Vit.B6, Vit.B12, red blood cell folates and urinary delta-aminolevulinic
acid (ALA) and porphobilinogen(PBG) levels (mean of six measurements).
Results
Symptomatic AP patients had significantly higher urinary ALA and PBG levels, plasma
Hcy, HHcy prevalence and Hcy/Cys ratio when compared to asymptomatic carriers of AP.
Even though no significant correlation was observed between ALA/PBG urinary levels
and serum Hcy levels, patients with higher levels of ALA and PBG had significantly
higher levels of Hcy, a higher prevalence of moderate-to severe HHcy and serum PLP
levels below the 25th percentile of a reference assessment with 300 healthy Italian subjects(<45nmol/L).
Conclusions
Most patients with symptomatic AP present HHcy resulting from alterations in sulphur
amino acid metabolism. HHcy may represent an indirect marker of ALAS1 induction and
its prevalence may be suggestive of a role of HHcy in the pathogenesis and/or comorbidities
of AP.
Keywords
Abbreviations:
AIP (Acute Intermittent porphyria), ALA (delta aminolevulinic acid), ALAS1 (5-aminolevulinate synthase 1), AP (Acute Porphyrias), APA (Acute Porphyric Attack), CBS (Cystathionine beta-Synthase), CGL (cystathionine γ-lyase), Cys (Cysteine), Hcy (Homocysteine), HHcy (Hyperhomocysteinemia), MTHFR (Methylene-Tetrahydrofolate Reductase), PBG (Porphobilinogen), PLP (Pyridoxal-phosphate), VP (Variegate Porphyria)To read this article in full you will need to make a payment
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References
- Lancet. 2005; 365: 241-252
- Porphyrias.Lancet. 2010; 375 (https://doi.org/S0140-6736(09)61925-5 [pii]): 924-937https://doi.org/10.1016/S0140-6736(09)61925-5
- The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine.Internal and emergency medicine. 2009; 4: 297-308
- The Acute Porphyric Attack: A Difficult Diagnosis for a Potential Lethal Event in Emergency Medicine.J Emerg Med Trauma Surg Care. 2015; 1: 7-16
- The acute porphyrias.Lancet. 1997; 349: 1613-1617
- The biochemistry of heme biosynthesis.Archives of biochemistry and biophysics. 2008; 474: 238-251
- Structure and function of enzymes in heme biosynthesis.Protein science: a publication of the Protein Society. 2010; 19: 1137-1161
- Homocysteine metabolism.Annu Rev Nutr. 1999; 19: 217-246
- Methionine metabolism in mammals.J Nutr Biochem. 1990; 1: 228-237
- The metabolism of homocysteine: pathways and regulation.Eur J Pediatr. 1998; 157: S40-S44
- Hyperhomocysteinemia: an independent risk factor for vascular disease.N Engl J Med. 1991; 324: 1149-1155
- Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.N Engl J Med. 1996; 334: 759-762
- Hyperhomocysteinemia and venous thrombosis: a meta-analysis.Thromb Haemost. 1998; 80: 874-877
- Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.N Engl J Med. 2002; 346: 476-483
- Homocysteine and B vitamins in mild cognitive impairment and dementia.Clinical chemistry and laboratory medicine: CCLM / FESCC. 2005; 43: 1096-1100
- Homocysteine and neurologic disease.Archives of neurology. 2000; 57: 1422-1427
- Homocysteine and vascular disease.Nat Med. 1996; 2: 386-389
- Metabolic evidence that deficiencies of vitamin B-12 (cobalamin), folate, and vitamin B-6 occur commonly in elderly people.The American journal of clinical nutrition. 1993; 58: 468-476
- Concentrations of total homocysteine in plasma in chronic renal failure.Clinical chemistry. 1990; 36: 2137-2138
- Hyperhomocysteinaemia in chronic liver diseases: role of disease stage, vitamin status and methylenetetrahydrofolate reductase genetics.Liver Int. 2005; 25: 49-56
- Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases.Atherosclerosis. 1999; 143: 163-170
- Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR).Thromb Haemost. 1997; 78: 523-526
- Disorders in transulfuration.in: Stanbury JB WJ Fredrickson DS Goldstein JL Brown MS Metabolic Bases of inherited diseases. McGraw-Hill Boo, New York, NJ1995: 1279-1327
- Transsulfuration depends on heme in addition to pyridoxal 5′-phosphate. Cystathionine beta-synthase is a heme protein.The Journal of biological chemistry. 1994; 269: 25283-25288
- Hyperhomocysteinemia: a biochemical surrogate in acute porphyrias with peripheral neuropathy?.in: Porphyrins and Porphyrias Meeting Stockholm. 2009
- Preliminary report: hyperhomocysteinemia in patients with acute intermittent porphyria.Metabolism: clinical and experimental. 2010; 59: 1809-1810
- Plasma vitamin B-6 forms and their relation to transsulfuration metabolites in a large, population-based study.The American journal of clinical nutrition. 2007; 86: 131-138
- Relationships among plasma homocysteine, cysteine, and albumin concentrations: potential utility of assessing the cysteine/homocysteine ratio.Clinical chemistry. 2001; 47: 1121-1124
- Cystathionine-beta-synthase deficiency: detection of heterozygotes by the ratios of homocysteine to cysteine and folate.Metabolism: clinical and experimental. 1998; 47: 207-211
- Modification of a high-performance liquid chromatographic method for assay of homocysteine in human plasma.J Chromatogr. 1993; 617: 136-139
- Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.N Engl J Med. 1985; 313: 709-715
- Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease.Effects of pyridoxine and folic acid treatment. Atherosclerosis. 1990; 81: 51-60
- Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease.Annu Rev Nutr. 1992; 12: 279-298
- A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.Nat Genet. 1995; 10: 111-113
- Diagnosis of acute intermittent porphyria in northern Sweden: an evaluation of mutation analysis and biochemical methods.Journal of internal medicine. 1995; 237: 301-308
- High-performance thin-layer chromatography of free porphyrins for diagnosis of porphyria.Clinical chemistry. 1994; 40: 2026-2029
- Vitamin B6 and oxalic acid in clinical nephrology.J Ren Nutr. 2010; 20: S95-102
- Kidney damage in acute intermittent porphyria.Przegl Lek. 2011; 68: 610-613
- Pyridoxal phosphate in acute intermittent porphyria.Annals of the New York Academy of Sciences. 1969; 166: 361-364
- Impaired vitamin B6-status in patients with acute intermittent porhyria.International Congress on Porphyrins and Porphyrias. 2017; (Bordeaux2017. p. 64.)
- Effect on dietary pyridoxine deficiency on experimental porphyria.Metabolism: clinical and experimental. 1970; 19: 189-191
- Methionine metabolism in liver diseases.The American journal of clinical nutrition. 2003; 77: 1094-1095
- Accumulation of homocyst(e)ine in vitamin B-6 deficiency: a model for the study of cystathionine beta-synthase deficiency.The Journal of nutrition. 1982; 112: 1264-1272
- The effect of a subnormal vitamin B-6 status on homocysteine metabolism.J Clin Invest. 1996; 98: 177-184
- Vitamin B6 in clinical neurology.Annals of the New York Academy of Sciences. 1990; 585: 250-260
- Experimental model of pyridoxine (B6) deficiency-induced neuropathy.Ann Plast Surg. 2001; 47: 153-160
- The nature of the neuropathy complicating acute intermittent porphyria.Lancet. 1967; 2: 1023-1024
- Vitamin nutrition status and homocysteine: an atherogenic risk factor.Nutr Rev. 1994; 52: 383-387
- Hyperhomocysteinemia and related factors in 600 hospitalized elderly subjects.Metabolism: clinical and experimental. 2001; 50: 1466-1471
- Assessing nutritional status of acute intermittent porphyria patients.European journal of clinical investigation. 2012; 42: 943-952
- Hereditary coproporphyria.Br Med J. 1955; 2: 85-88
- The etiology of the neuropathy in acute intermittent porphyria.Trans Am Neurol Assoc. 1968; 93: 294-296
- Effect of pyridoxine deficiency on porphyrin precursor excretion in acute intermittent porphyria.Am J Med. 1966; 41: 369-374
- Folate deficiency and acute intermittent porphyria in a 12-year-old boy.Neurology. 1993; 43: 1438-1439
- Ascorbic acid deficiency in porphyria cutanea tarda.J Lab Clin Med. 1997; 130: 197-201
- Vitamin D deficiency in patients with erythropoietic protoporphyria.Journal of inherited metabolic disease. 2010; 33: S1-S4
- Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics.Journal of internal medicine. 2011; 269: 278-288
- Liposoluble vitamins and naturally occurring carotenoids in porphyria cutanea tarda.European journal of clinical investigation. 1995; 25: 510-514
- Porphyrin biosynthesis in Euglena gracilis–IV. an endogenous factor controlling the enzymic synthesis of porphyrinogens and its possible role in the treatment of some porphyrias.Int J Biochem. 1981; 13: 343-353
- Two genes encode distinct glutamate decarboxylases.Neuron. 1991; 7: 91-100
- Delta-Aminolevulinic acid: influences on synaptic GABA receptor binding may explain CNS symptoms of porphyria.Ann Neurol. 1977; 2: 340-342
- Porphyria.N Engl J Med. 2017; 377: 862-872
Article info
Publication history
Published online: May 31, 2020
Accepted:
April 1,
2020
Received in revised form:
March 19,
2020
Received:
September 3,
2019
Identification
Copyright
© 2020 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
