The roles of iron in health and disease

Recent advances in the molecular understanding of the porphyrias now offer specific diagnosis and precise definition of the types of genetic mutations involved in the disease. Molecular diagnostic testing is powerful and very useful in kindred evaluation and genetic counselling when a disease-responsible mutation has been identified in the family. It is also the only way to properly screen asymptomatic gene carriers, facilitating correct treatment and appropriate genetic counselling of family members at risk. However, it should be noted that DNA-based testing is for the diagnosis of the gene carrier status, but not for the diagnosis of clinical syndrome or severity of the disease, e.g. an acute attack. For the diagnosis of clinically expressed porphyrias, a logical stepwise approach including the analysis of porphyrins and their precursors should not be underestimated, as it is still very useful, and is often the best from the cost-effective point of view.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.2006.06289.x

Modern diagnosis and management of the porphyrias

Acute intermittent porphyria (AIP) is due to a deficiency of the third enzyme, the hydroxymethylbilane synthase, in heme biosynthesis. It manifests with occasional neuropsychiatric crises associated with overproduction of porphyrin precursors, aminolevulinic acid and porphobilinogen. The clinical criteria of an acute attack include the paroxysmal nature and various combinations of symptoms, such as abdominal pain, autonomic dysfunction, hyponatremia, muscle weakness, or mental symptoms, in the absence of other obvious causes. Intensive abdominal pain without peritoneal signs, acute peripheral neuropathy, and encephalopathy usually with seizures or psychosis are the key symptoms indicating possible acute porphyria. More than fivefold elevation of urinary porphobilinogen excretion together with typical symptoms of an acute attack is sufficient to start a treatment. Currently, the prognosis of the patients with AIP is good, but physicians should be aware of a potentially fatal outcome of the disease. Mutation screening and identification of type of acute porphyria can be done at the quiescent phase of the disease. The management of patients with AIP include following strategies: A, during an acute attack: 1) treatment with heme preparations, if an acute attack is severe or moderate; 2) symptomatic treatment of autonomic dysfunctions, polyneuropathy and encephalopathy; 3) exclusion of precipitating factors; and 4) adequate nutrition and fluid therapy. B, during remission: 1) exclusion of precipitating factors (education of patients and family doctors), 2) information about on-line drug lists, and 3) mutation screening for family members and education about precipitating factors in mutation-positive family members. C, management of patients with recurrent attacks: 1) evaluation of the lifestyle, 2) evaluation of hormonal therapy in women, 3) prophylactic heme therapy, and 4) liver transplantation in patients with severe recurrent attacks. D, follow-up of the AIP patients for long-term complications: chronic hypertension, chronic kidney insufficiency, chronic pain syndrome, and hepatocellular carcinoma.

/pdf/an-update-of-clinical-management-of-acute-intermittent-44qgiihdvy.pdf

An update of clinical management of acute intermittent porphyria.

Acute porphyrias are rare inherited disorders due to deficiencies of haem synthesis enzymes. To date, all UK cases have been one of the three autosomal dominant forms, although penetrance is low and most gene carriers remain asymptomatic. Clinical presentation is typically with acute neurovisceral attacks characterised by severe abdominal pain, vomiting, tachycardia and hypertension. Severe attacks may be complicated by hyponatraemia, peripheral neuropathy sometimes causing paralysis, seizures and psychiatric features. Attacks are triggered by prescribed drugs, alcohol, hormonal changes, fasting or stress. The diagnosis is made by finding increased porphobilinogen excretion in a light-protected random urine sample. Management includes administration of intravenous human haemin and supportive treatment with non-porphyrinogenic drugs. A few patients develop recurrent attacks, a chronic illness requiring specialist management. Late complications include chronic pain, hepatocellular carcinoma, chronic renal failure and hypertension. In the UK, the National Acute Porphyria Service provides clinical advice and supplies haemin when indicated.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjh.14459

Update review of the acute porphyrias.

Porphyria diseases are a group of metabolic disorders caused by abnormal functioning of heme biosynthesis enzymes and characterized by excessive accumulation and excretion of porphyrins and their precursors. Precisely which of these chemicals builds up depends on the type of porphyria. Porphyria is not a single disease but a group of nine disorders: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), δ-aminolevulinic acid dehydratase deficiency porphyria (ADP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLP). Each porphyria results from overproduction of heme precursors secondary to partial deficiency or, in XLP, increased activity of one of the enzymes of heme biosynthesis. Taken together, all forms of porphyria afflict fewer than 200,000 people in the United States. Based on European studies, the most common porphyria, PCT, has a prevalence of 1 in 10,000, the most common acute porphyria, AlP, has a prevalence of ∼1 in 20,000, and the most common erythropoietic porphyria, EPP, is estimated at 1 in 50,000 to 75,000. CEP is extremely rare, with prevalence estimates of 1 in 1,000,000 or less. Only six cases of ADP are documented. The current porphyria literature is very exhaustive and a brief overview of porphyria diseases is essential in order for the reader to better appreciate the relevance of this area of research prior to undertaking biochemical diagnostics procedures. This unit summarizes the current knowledge on the classification, clinical features, etiology, pathogenesis, and genetics of porphyria diseases.

Porphyria Diagnostics—Part 1: A Brief Overview of the Porphyrias

“Ethanol should be included in the list of drugs metabolized by hepatic microsomes” (Rubin and Lieber 1972) Such drugs stimulate their own metabolism, in which heme synthesis is involved, and affect porphyrin synthesis in various ways Alteration of porphyrin synthesis in an organism without hereditary and acquired toxic disturbances of porphyrin metabolism is an adaptive response Generally, these adaptive responses elicited by alcohol or other drugs in an organism without preexistent derangements in the heme biosynthesis sequences do not lead to clinical consequences However, certain drugs, including alcohol, are capable of expressing not only the latent but also the clinical phase of different porphyrias Especially acute hepatic porphyrias are triggered by drugs and/or alcohol and have therefore been designated as “pharmacogenetic diseases” (Kalow 1962) In addition, alcohol is the most frequent manifesting and aggravating factor in chronic hepatic porphyria, including porphyria cutanea tarda, which is genetically predetermined in some of the patients (Doss 1982; Kushner 1982) The clinical-biochemical interactions between alcohol and porphyrin/heme biosynthesis involve three main aspects: 

1

Triggering the biochemical and clinical manifestation of acute and chronic hepatic porphyrias




2

Development of symptomatic disturbances in porphyrin metabolism as secondary coproporphyrinuria and secondary protoporphyrinemia




3

Inhibition and stimulation of certain enzymes in the heme biosynthetic chain

/pdf/alcohol-and-porphyrin-metabolism-3z8a2vba07.pdf

Alcohol and porphyrin metabolism.

Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients

Studies on coproporphyrin isomers in urine and feces in the porphyrias.

Hintergrund: Duale Porphyrien sind durch die Koexistenz zweier unabhangiger Porphyrinstoffwechselstorungen charakterisiert. Patient und Methoden: Bei einer 26-jahrigen Patientin mit Ruckenschmerzen und rotem Urin wurde zunachst eine Porphyria cutanea tarda und durch weitere Untersuchungen eine hereditare Koproporphyrie diagnostiziert. Die Metaboliten des Porphyrinstoffwechsels wurden chromatographisch analysiert. Die Aktivitaten der Koproporphyrinogenoxidase und der Uroporphyrinogendecarboxylase wurden in Blutzellen bestimmt. Die molekulare Analyse erfolgte mittels denaturierender Gradientengelelektrophorese, gefolgt von direkter Sequenzierung. Ergebnisse: Eine exzessiv hohe Porphyrinurie von 3 128 nmol/24 h (normal < 165 nmol/24 h) mit Dominanz von Uro- und Heptacarboxyporphyrin (75% der Gesamtporphyrine) wies bei der Patientin auf eine Porphyria cutanea tarda hin. Verlaufsuntersuchungen zeigten eine Konstellationsanderung mit Dominanz von Koproporphyrinisomer III in Urin und Stuhl, die fur eine hereditare Koproporphyrie charakteristisch ist. Prophyrinvorlaufer und Porphyrine stiegen unter Einnahme von Ethinylestradiol-Cyproteronacetat an. Neben erhohtem Uro- und Heptacarboxyporphyrin im Urin blieb die Dominanz von Koproporphyrinisomer III im Stuhl konstant. Die Aktivitat der Koproporphyrinogendecarboxydase war um 35% vermindert. Die erythrozytare Uroporphyrinogendecarboxylase war normal. Die Mutter und beide Schwestern wurden als heterozygote Gentrager einer hereditaren Koproporphyrie in der Latenzphase aufgrund eines Anstiegs des Koproporphyrins mit Isomer-I/III-Inversion im Stuhl und einer Minderung der Koproporphyrinogenoxidase-Aktivitat um etwa 50% erkannt. Molekulargenetische Analysen ergaben eine Punktmutation im Exon 4 (854C→T) des Koproporphyrinogenoxidase-Gens, die einen Aminosaurenaustausch (P258L) im Koproporphyrinogenoxidase-Protein zur Folge hat. Schlussfolgerung: Bei einer dualen Porphyrie mit Koexistenz von Porphyria cutanea tarda und hereditarer Koproporphyrie ist die hereditare Koproporphyrie durch eine neue Mutation im Koproporphyrinogenoxidase-Gen bedingt. Die Porphyria cutanea tarda, als sporadische hepatische Form Typ I, ist ostrogeninduziert. Die grosen exkretorischen Variationen reflektieren den Einfluss hormonaler Faktoren auf den hepatischen Porphyrieprozess von hereditarer Koproporphyrie und Porphyria cutanea tarda.

Koexistenz von hereditärer Koproporphyrie und Porphyria cutanea tarda: Eine neue Form einer dualen Porphyrie

A 27-year-old woman who had recurrent pain in renal bed since 1998 with increasing character, was stationary admitted. The patient showed dark urine, complained of hair loss and took since 1994 a hormonal oral contraceptive. No photosensitivity was observed. Determinations of urinary porphyrin metabolites in 1998 revealed a porphyria cutanea tarda like excretion pattern with elevations of uro- (1767 nmol/24 hr, normal <29 nmol/24 hr) and heptacarboxyporphyrin (568 nmol/24 hr; normal <4 nmol/24 hr). Follow-up studies in feces showed the characteristics of a hereditary coproporphyria with dominance of coproporphyrin isomer III (total= 1470 nmol/g, isomer III= 93%), (normal: <37 nmol/g, isomer III = 25-35%). The excretion of porphyrin precursors (delta-aminolevulinic acid and porphobilinogen) was increased by taking an ethinylestradiol-cyproteronacetate-preparation, but acute and/or chronic manifestations were not observed. Coproporphyrinogen oxidase activity was decreased to 35% in the patient (normal=138+/-21 pkat/g protein; x+/-s), whereas the activity of red cell uroporphyrinogen decarboxylase was normal. Her mother and both sisters could be verified as heterozygous gene carriers of hereditary coproporphyria by their urinary and fecal excretion parameters and because of reduced coproporphyrinogen oxidase activity up to 50%. The father was normal with respect to his genotype. Molecular analysis revealed a hitherto unknown mutation with the transversion of a cytosine to thymine at nucleotide position 854 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by DGGE in the mother and her three daughters. The investigation of the immunological nature of the defective coproporphyrinogen oxidase gene from the whole family revealed decreased concentrations of coproporphyrinogen oxidase protein in the patient, her mother and her two sisters.

Alexandra Kühnel

Papers

Alcohol and porphyrin metabolism.

Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients

Studies on coproporphyrin isomers in urine and feces in the porphyrias.

Koexistenz von hereditärer Koproporphyrie und Porphyria cutanea tarda: Eine neue Form einer dualen Porphyrie

Molecular, immunological, enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary coproporphyria.