Porphyrias: diseases related to heme biosynthesis

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      Congenital or acquired disturbances of heme biosynthesis are called porphyrias. The reason why these disturbances may be congenital or acquired is that the same enzyme may be mutated or, in some cases, may be inhibited by exernal poisons, usually as a result of professional intoxications. The heme (iron protoporphyrin IX) is the prostethic group of hemoglobin and myoglobin; heme variants are present in many respiratory enzymes. The heme is so important that absence of its biosynthesis is incompatible with life. As a consequennce in porphyrias the biosynthesis is deranged but not blocked (as blockage would cause intrauterine death at an early stage of embrionic development rather than a congenital disease), and symptoms are due to accumulation of wrong products or precursors in the tissues. Heme precursors or wrong metabolytes accumulate mainly in the skin, causing cutaneous porphyrias and/or in the peripheral nerves, causing neurological porphyrias.

Audio: definition of porphyrias

      The main clinical symptom of cutaneous porphyrias is photosensytivity; the main symptom of neurological porphyrias is pain. The following table collects the different types of porphyrias, ordering them according to their main symptoms: neurological, mixed, and cutaneous.
DiseaseEnzymatic defectInheritance Symptoms
Acute Intermittent P.Uroporphyrinogen synthase Dominant Neu
Hereditary CoproporphyriaCoproporphyrinogen oxidase Dominant (Skin)/Neu
Variegate P.Protoporphyrinogen oxidase Dominant (Skin)/Neu
Congenital Erythropoietic P.Uroporphyrinogen III cosynthase Recessive Skin
P. cutanea tardaUroporphyrinogen decarboxylase Dominant or acquired Skin
Erythropoietic ProtoporphyriaFerrochelatase Dominant Skin
Symptoms: skin=major cutaneous lesions due to photosensitivity; Neu=neurological symptoms (mainly pain); (Skin)/Neu=minor cutaneous symptoms associated to major neurological symptoms
Pay attention not to confuse the similarly named congenital erythropoietic porphyria and erythropoietic PROTOporphyria!

Audio: classification of porphyrias

      In order to properly locate each disease along the heme biosynthesis pathway, and thus to identify the precursor(s) that accumulate, or the wrong metabolyte(s) that may be produced you may refer to the following picture that summarizes the complex sequence of reactions that, starting from glycine and succinyl-CoA, leads to heme biosynthesis.

Audio: heme biosynthesis

      It is important to recall that porphyrins and their precursors are poorly soluble in water, thus urinary excretion is usually insufficient, and accumulation in the tissues occurs. Indeed elimination of heme catabolytes: (i) requires degradation to biliverdin, and then to bilirubin, followed by conjugation to glucuronic acid to increase bilirubin's solubility; and (ii) is mainly via the faeces, where solubility is a minor concern. Our organism has scarce capability of disposing of heme precursors, as these are poor substrates for heme oxygenase, the enzyme that converts heme to biliverdin.

      Porphyrias are either genetic or acquired diseases. Genetic porphyrias are due to the patient inheriting a poorly functioning or unstable variant of one of the enzymes involved in the biosynthesis of the heme. Acquired porphyrias are usually due to intoxication with substances capable of inactivating the same enzymes (e.g. chronic lead intoxication; chronic alcholism). Depending on the enzyme affected, and the intermediate which is accumulated, one may distinguish between cutaneous and hepatic/neurological porphyrias.
      Two types of porphyrias are particularly noteworthy. Congenital erythropoietic porphyria, is due to a defect of uroporphyrinogen III cosynthase. This enzyme guarantees the appropriate orientation of the pyrroles in the biosynthesis of uroporphyrinogen III. In the absence of the enzyme, uroporphyrinogen synthase produces some uroporphyrinogen III and some of its isomers, differing in the position of acetate and propionate side chains, that cannot be used in the heme biosynthesis and accumulate. This is the most severe form of cutaneous porphyria. Congenital protoporphyria is interesting because it leads to accumulation of iron-free protoporphyrin IX that should be recognized as a substrate by heme oxygenase; however the substance accumulates not only in the erythrocytes, but also in tissues where it is not metabolyzed to biliverdin, e.g. in the liver, and this may lead to progressive liver failure.

      Most porphyrias are hereditary and dominant; thus, multiple cases occur among the patient's relatives, and the familial anamnesis provides important diagnostic clues.
      Cutaneous porphyrias are easily suspected on a purely clinical basis. Porphyrin precursors accumulate in the skin and, given their florescence properties, they harvest sun light and transfer the radiant energy to the surrounding cells causing damage of the DNA (e.g. dimerization of timine) and necrosis. The resulting dermatitis is severe, with extensive ulcerations. The patient becomes aware of his/her condition in the early infancy and avoids direct sunlight: he/she leaves home after sunset and uses extensive clothing.

      A cardinal sign of erythropoietic congenital porphyria is erythrodonthia, a reddish coloration of the teeth, due to accumulation of porphyrinogens in the teeth. Illumination with blue light reveals the reddish fluorescence of the teeth and is of diagnostic value (no other disease causes this phenomenon).

Audio: cutaneous porphyrias

      By contrast, neurological porphyrias are difficult to diagnose on clinical grounds alone. The chief manifestation is pain, due to peripheral neuropathy. Pain occurs suddenly in acute crises and is frequently misdiagnosed as an acute abdominal condition. Given the intensity of the syndrome, these patients often undergo repeated surgeries, because of suspected appendicitis, volvulus, biliary or urinary calculi, etc. Needless to say none of these conditions is the culprit, even though all of them may occasionally co-exist. The most dramatic cases are those caused by acute intermittent porphyria. Neurological porphyrias must be differentiated from: (i) acute abdominal conditions requiring surgery; and (ii) other non surgical conditions such as tabes dorsalis or the colica saturnina (in the course chronic lead poisoning).

      Diagnosis of porphyrias is based on the demonstration of the increased concentration of one of the heme precursors in the serum or in the urine. These compounds are strongly fluorescent, and in acidic medium (HCl), they react with benzaldehyde derivatives (Ehrlich reaction) to yield a characteristic purplish pigment. If the biological sample is positive to these simple test, identification of the specific porphyrin can be achieved by chromatography.
Laboratory diagnostic features of porphyrias
Porphyriaurine ALA and PBGurine porphyrinsfecal porphyrinsred blood cell porphyrins
Acute intermittent porphyria increased increased uroporphyrinogen normal normal
Hereditary coproporphyria increased increased coproporphyrinogen increased coproporphyrinogen normal
Variegate porphyria increased increased coproporphyrinogen increased coproporphyrinogen and protoporphyrin normal
Congenital erythropoietic porphyria normal increased uroporphyrinogen and coproporphyrinogen increased coproporphyrinogen increased uroporphyrinogen and coproporphyrinogen
Porphyria cutanea tarda normal increased uroporphyrinogen increased isocoproporphyrin normal
Erythropoietic Porphyria normal normal increased coproporphyrinogen increased uroporphyrinogena and coproporphyrinogen

      We remark that:
(i) in neurological porphyrias the urinary excretion of porphobilinogen (PBG) is increased (not so in cutaneous porphyrias). The normal value of PBG in the urine of healthy humans is <2.5 mg/die or <2 mg/L (in a random urine sample). During acute attacks of neurological porphyrias the patient may excrete >50 mg/die of PBG in the urine.
(ii) in cutaneous porphyrias, with the exception of porphyria cutanea tarda, the red blood cells contain porphyrinogens, which are absent in neurological porphyrias and in healthy subjects.
(iii) Gene sequencing may be carried out to confirm the diagnosis, but the biochemical laboratory tests should be first carried out, in order to reduce the number of genes to be sequenced.
      The differential diagnosis of cutaneous porphyrias is relatively simple: few diseases cause such severe damage of the skin exposed to sunlight. Dermatological diseases may be aggravated by exposure to sunlight, but most often are not limited only to the light-exposed areas, whereas skin lesions due to cutaneous porphyrias only affect exposed areas. Autoimmune diseases such as lupus erythematosus may cause skin lesions in the light-exposed areas, but these are less severe than those observed in porphyrias, and are associated to other symptoms (e.g. renal malfunctiong) which are absent in porphyrias. The laboratory demonstration of heme precursors in the blood and urine confirms the diagnosis.

Audio: differential diagnosis of cutaneous porphyrias

      The differential diagnosis of neurological porphyrias is difficult, and many more common diseases may cause acute crises of abdominal pain. The first point the physician should address is whether the patient's symptoms indicate that peritoneal involvement is present (this usually suggests a surgical condition) or not (usually indicating a medical condition). An indicative diagnostic flow-chart is reported in the figure below.

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