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Diseases associated with impaired heme and porphyrin metabolism

  • Diseases associated with impaired heme and porphyrin metabolism

    Thalassemia is a heterogeneous group of genetic disorders associated with impaired synthesis of normal Hb polypeptide chains. These anomalies lead to the development of hypochromic microcytic anemias of varying severity. Decrease in the synthesis of a-globin chains causes a-thalassemia, P-chains - p-thalassemia. The human has two identical a-globin genes on each chromosome 16 and one P-globin gene on the chromosome 11.

    Most cases of a-thalassemia are due to the deletion of genes controlling the synthesis of a-globin chains. The severity of a-thalassemia is related to the number of deletions of these genes. Deletion of one gene is not clinically apparent. With the deletion of two genes, mild anemia is possible with a decrease in MCV.The results of Hb electrophoresis are normal. DNA diagnosis methods are used to establish the diagnosis. With the loss of 3 genes, anemia of varying severity develops with an Hb content of 70-90 g / l. When electrophoresis is detected, HbH Deletion of all 4 genes leads to a fetal incompatible with life.

    P-Thalassemia( * 141900, 11p15.5, more than 90% of all thalassemias) develops as a result of expression of abnormal genes of the p-globin chain. Small R-thalassemia occurs in individuals heterozygous for a pathological gene. Most of them have no clinical manifestations, but they reveal red blood cell hypochromia and a decrease in MCV.The diagnosis is confirmed by electrophoresis Hb( increased content of HbA2 and / or HbF).Large p-thalassemia( Cooley's anemia) develops in individuals homozygous for a pathological gene. Already in the first year of life develops severe hypochromic microcytic anemia. Treatment includes regular blood transfusions in combination with the administration of iron-binding drugs or a red bone marrow transplant.

    Porphyria is a group of heterogeneous, predominantly hereditary diseases, which are based on disturbances in biosynthesis of heme and accumulation in the body of porphyrins and / or their precursors.

    The synthesis of heme occurs in 8 steps, each of which requires a specific enzyme. A key role is played by the enzyme of the first stage - synthetase of aminolevulinic acid, the regulation of its activity limits the rate of heme synthesis. Under the influence of inducing factors, the activity of this enzyme can increase 5-6 times, and when the final product( heme) is accumulated, it decreases.

    The form of porphyria is determined by the inadequacy of one of the 8 specific enzymes in the heme synthesis chain. Enzymatic block at any level of this chain leads to a decrease in the amount of heme and causes an increase in the activity of synthetase of aminolevulinic acid. As a result, the synthesis products accumulate before the blocked section of the chain.

    Depending on where the increased formation and accumulation of porphyrins and their predecessors takes place, porphyria is divided into hepatic and erythropoietic. In most cases, the enzymatic defect is expressed in all tissues, so it is more correct to talk only about the primary involvement in the process of either the liver or bone marrow. The reference values ​​for porphyrin concentrations are given in the table.

    Table Reference concentrations of porphyrins in blood [Henry JD, 1996]

    Table Reference concentrations of porphyrins in blood [Henry JD, 1996]


    According to the clinical course, porphyria is divided into acute( OPP, hereditary coproporphyriaand others) and chronic( congenital porphyry, skin hepatic porphyria, etc.).

    The most common variant is OPP( frequency is approximately 1:30 000) due to the deficiency of hydroxymethylbilane synthetase, porphobilin deaminase or uroporphygene synthase( * 176000, 11q23.3, defects in HMBS, PBGD, UPS).

    In 70-90% of carriers of a pathological gene, no clinical manifestations occur in life. In other cases, the disease is manifested by attacks of acute pain in the abdomen, lesions of the peripheral( polyneuropathy) and central( seizures, epileptiform seizures, delusions, hallucinations) of the nervous system, provoked by the adoption of a number of drugs and hormonal drugs, and various stresses, with possible fatal outcomeapproximately 60%).OPP refers to the group of acute hepatic porphyria.

    A presumptive diagnosis of acute porphyria can be made based on the appearance of colored urine during an attack( from slightly pink to reddish-brown).The pink color of urine is due to the increased content of porphyrins in it, and the red-brown color is due to the presence of pro-toporphine, a product of porphobilinogen degradation. To confirm the diagnosis, a complex of biochemical and genetic studies is carried out.

    At the first stage, urine is examined for the presence of excess porpho- bilinogen in it - a qualitative screening test with Ehrlich's reagent, or

    58-aminolevulinic acid( 5-ALA).Porphobilinogen, reacting with Ehrlich's reagent, forms a colored pink-red color product in an acidic solution. This test is almost always positive for acute attacks of porphyria and only in rare cases it is false positive. The negative test result does not allow to exclude the diagnosis of acute porphyria. This is due to a number of reasons: urine may contain inhibitory substances that cause a false-negative result;an increase in the concentration of porphobilinogen may be insignificant( below the sensitivity limit of the method);the excretion of porphobilinogen can rapidly decrease and normalize within a few days after an acute attack. In this regard, all positive and some negative( in the presence of an appropriate clinical picture of the disease) test results should be confirmed by quantitative determination of porphobilinogen in the urine. Given that in some cases, in the OPP, the content of 5-ALA first increases sharply, it is necessary to carry out a study on 5-ALA in the presence of clinical symptoms and a negative test for porphobili-nogen.

    Normally, the concentration of porphobilinogen in urine is less than 2 mg / L.When obtaining normal results of quantitative determination of porphyrinogen in the urine, porphyria as the cause of acute symptoms can in most cases be rejected. Patients with an increased concentration of PHB in urine are diagnosed with "acute porphyria" and further perform research on differential diagnosis of OPP and other forms of acute porphyria. For this purpose, the definition of total porphyrins in feces is used.

    Normally, the concentration of total porphyrins in stool is less than 200 mmol / kg of dry stool. The normal concentration of total porphyrins in the feces confirms the diagnosis of OPP.With varigate porphyria and congenital protoporphyria, this concentration increases many times.

    Thus, the diagnosis of OPP during the acute course of the disease can be established on the basis of an increased concentration of porphobile-nails in the urine and the normal content of total porphyrins in the feces. Outside the exacerbation and in asymptomatic cases, the elevated content of porpho- bilinogen in urine is detected only in 30% of patients with OPP.In such cases it is necessary to carry out a study of the activity of porphobilinogen deaminase in erythrocytes.

    Porphobilinogen deaminase is a cytoplasmic enzyme that catalyzes the condensation of four molecules of porphobilinogen to form linear tetrapyrrole. The enzyme exists in two isoforms, one of which is specific for erythrocytes, and the other is contained in the cells of virtually all tissues. Normally, the activity of porphobilinogen deaminase in erythrocytes is 5.8-11.7 nmol / s / l [Tiz N., 1997].Approximately 90% of patients with OPP enzyme activity in erythrocytes is reduced by 2 times. In approximately 5% of patients, the activity of porphobilinogen deaminase can be within normal limits because of overlap in levels of enzyme activity in normal and in OPP.In such cases, an accurate diagnosis can be made only using molecular genetic methods. The informativeness of the various diagnostic methods of

    OPP depending on the period of the disease is presented in Tables-10-7, and in Fig.the algorithm for diagnosing the disease is given. The gene porphobilin-deaminase gene is localized on chromosome 11( 11q23-11qter).For the detection of mutations, the DNA of the lymphocytes of the patients is examined by PCR, sequencing or RFLP analysis.


    Fig. Algorithm of examination of patients with suspected porphyria

    Fig. Algorithm for the examination of patients with suspected porphyria

    Table Informativeness of various diagnostic methods of OPP depending on the period of the disease


    Table Typical biochemical changes associated with impaired metabolism of porphyrin [Henry J. D., 1996]


    Notes: UE - uroporphyrin;KP - coproporphyrin;PP - protoporphyrin;5-ALA-58-aminolevulinic acid;PBG - porphobilinogen;T - increase;TT - a significant increase;H is the norm.

    Notes: UE - uroporphyrin;KP - coproporphyrin;PP - protoporphyrin;5-ALA-58-aminolevulinic acid;PBG - porphobilinogen;T - increase;TT - a significant increase;H is the norm.