The Metabolism of the Heme


      The heme (iron protoporphyrin IX) is the prostethic group of hemoglobin and myoglobin; heme variants are present in many respiratory enzymes. The heme is synthesized in a complex sequence of reactions, starting from glycine and succinyl-CoA.

      Disturbances of heme biosynthesis are called porphyrias, and cause accumulation of some derivative of porphobilinogen and deficit of the final product. Symptoms are due to both the accumulation of the intermediate metabolyte and lack of the functional hemoproteins. 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 bilirubin and conjugation to glucuronic acid to increase its solubility; and (ii) is mainly via the faeces, where solubility is a minor concern (see below).

      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.
      The main clinical symptom of cutaneous porphyrias is photosensytivity; the main symptom of neurological porphyrias is pain.
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

      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. The disease is usually hereditary and multiple cases occur among his/her relatives. A cardinal sign of erythropoietic congenital porphyria is erythrodonthia reddish coloration of the teeth, due t accumulation of coproporphyrinogen in the tooth).
      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 of 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.
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