The Porphyrias

In mammalian tissues, usually the liver and the bone marrow, heme is 

Psychiatric disorders (in so far as they can be explained by imbalances in neurochemicals) that accompany some of the porph)oias may be caused by a build-up in levels of ALA, which bears a structural resemblance to the neurotransmitter GABA (y-aminobutyric acid), and so could act as a neurotoxin. The heme deficiency that is brought on by the porphyrias, can lead to a reduction in the activity of hepatic (liver) enzymes that require heme. For example, reduction in the level of hepatic tryptophan pyrrolase activity leads to a build-up in levels of the amino acids tryptophan and 5-hydroxy-tryptophan. Thus, a heme-deficient state in the liver could produce biochemical abnormalities capable of leading to neurological dysfunction, while heme deficiency in nerve tissue could directly alter nerve function. This has led to the treatment of severe neurological dysfunction by intravenous administration of heme compounds. 

Iron insertion is the final step of heme biosynthesis, and this is controlled by the enzyme ferrochelatase. This enzyme is located on the inner face of the mitochondrial inner wall and its failure to function properly leads to a condition called erythropoietic protoporphyria, which, because protoporphyrin IX builds up in the skin, leads to light sensitivity. Protoporphyrin is also found in the red blood cells, bile, and feces. The three porphyrias that arise due to genetic malfunction of the last three enzymes in heme biosynthesis have not yet been tracked down to specific genetic abnormalities. 

Other conditions, besides the porphyrias, are known that lead to small increases in urinary porphyrin excretion. Clinically, these are grouped under the heading of secondary porphyrinuria and they usually arise from certain anaemias and liver/bile disorders. Misdiagnosis with porphyria is avoided by measuring the amount of ALA and PEG in the patient s urine, as the levels in secondary porphyrinuria are normal. 

Lead poisoning can affect the heme metabolic pathway at several sites, and this generally leads to an increase in the zinc protoporphyrin level of red blood cells. In fact, by measuring the fluorescence emission from red cell zinc protoporphyrin, it is possible to screen large populations for lead poisoning. Other substances that can affect the Ever, producing porphyria-like symptoms, are barbiturates, DDT, and alcohol. 

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Knowledge of the biochemistry of the porphyrins and of heme is basic to understanding the varied functions of hemoproteins (see below) in the body. The porphyrias are a group of diseases caused by abnormalities in the pathway of biosynthesis of the various porphyrins. Although porphyrias are not very prevalent, physicians must be aware of them. A much more prevalent clinical condition is jaundice, due to elevation of bilirubin in the plasma. This elevation is due to overproduction of bilirubin or to failure of its excretion and is seen in numerous diseases ranging from hemolytic anemias to viral hepatitis and to cancer of the pancreas. 

The importance of some of these regulatory mechanisms is further discussed below when the porphyrias are described. 

The porphyrias are a group of disorders due to abnormalities in the pathway of biosynthesis of heme they can be genetic or acquired. They are not prevalent, but it is important to consider them in certain circumstances (eg, in the differential diagnosis of abdominal... 

Biochemistry Underlies the Causes, Diagnoses, Treatments of the Porphyrias... 

In general, the porphyrias described are inherited in an autosomal dominant manner, with the exception of congenital erythropoietic porphyria, which is inherited in a recessive mode. The precise abnormalities in the genes directing synthesis of the enzymes involved in heme biosynthesis have been determined in some instances. Thus, the use of appropriate gene probes has made possible the prenatal diagnosis of some of the porphyrias. 

Figure 32-11. Biochemical causes of the major signs and symptoms of the porphyrias.

It is hoped that treatment of the porphyrias at the gene level will become possible. In the meantime, treatment is essentially symptomatic. It is important for patients to avoid drugs that cause induction of cyto-... 

Anderson KE et al Disorders of heme biosynthesis X-linked sideroblastic anemia and the porphyrias. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001. 

Elder GH Haem synthesis and the porphyrias. In Scientific Foundations of Biochemistry in Clinical Practice, 2nd ed. Williams DL, Marks V (editors). Butterworth-Heinemann, 1994. 

Haem synthesis is a good example of a pathway that is partly compartmentalized. The pathway (Figure 5.16) occurs in all cell types for the production of respiratory cytochromes and begins within mitochondria but the majority of the reactions occur in the cytosol cell. Because mature red cells have no subcellular organelles, haem synthesis occurs only in early RBC progenitor cells. Although this is a relatively simple pathway, there are a number of well-known enzyme defects that cause a group of diseases called the porphyrias. 

There are a large number of hereditary or acquired disturbances of porphyrin synthesis, known as porphyrias, some of which can cause severe clinical pictures. Several of these diseases lead to the excretion of heme precursors in feces or urine, giving them a dark red color. Accumulation of porphyrins in the skin can also occur, and exposure to light then causes disfiguring, poorly healing blisters. Neurological disturbances are also common in the porphyrias. 

Biochemical and Clinical Aspects of the Porphyrias Richard D. Levere and Attallah Kappas... 

The porphyrias are a heterogeneous group of diseases of porphyrin metabolism characterized by a variety of dermatologic, neurologic, and psychological manifestations. 

For idiosyncratic, patient related adverse reactions, less confirmatory tests are available but the number is growing. Skin, blood and urine tests are available to confirm acute and chronic allergic reactions. Genetic tests can determine the susceptibility of individuals and includes general tests such as for the porphyrias and sickle cell anaemia, and specific tests for dmg metabolism, such as acetylator status... 

Minder El, Schneider-Yin X (2007) The porphyrias. In Rodes J, Benhamou JP, Blei A, Reichen J, Rizzetto M (eds) Textbook of Hepatology From Basic Science to Clinical Practice. Blackwell, Oxford UK, pp 1343-1351... 

Minder El, Schneider-Yin X (2002) The porphyrias. In Blau N, Duran M, Blaskovics ME, Gibson KM (eds) Physician s Guide to The Laboratory Diagnosis of Metabolic Diseases. Springer, Berlin, Heidelberg, New York, pp 593-613... 

Lim CK, Peters TJ (1984) Urine and faecal porphyrin profiles by reversed-phase high-performance liquid chromatography in the porphyrias. Clin Chim Acta 139 55-63 Minder El, Vuilleumier JP, Vonderschmitt DJ (1992) Prototype application of robot in the clinical laboratory enabling fully automated quantification of fecal porphyrins. Clin Chem 38 516-521... 

Porphyrias are caused by inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors (see Summary Figure 21.7). With the exception of congenital erythropoietic porphyria, which is a genetically recessive disease, all porphyrias are inherited as autosomal dominant disorders. The mutations that cause the porphyrias are heterogenous (not all are at the same DNA locus), and nearly every affected family has its own mutation. Each porphyria results in the accumulation of a unique pattern of intermediates caused by the deficiency of an enzyme in the heme synthetic pathway. 

Clinical manifestations The porphyrias are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in the erythropoietic cells of the bone marrow or in the liver. Hepatic porphyrias can be further classified as acute or chronic. Individuals with an enzyme defect leading to the accumulation of... 

Increased ALA synthase activity One common feature of the j porphyrias is a decreased synthesis of heme. In the liver, heme normally functions as a repressor of ALA synthase. Therefore, Ihe absence of this end product results in an increase in the synthesis of ALA synthase (derepression). This causes an increased syn thesis of intermediates that occur prior to the genetic block. The accumulation of these toxic intermediates is the major pathophysi ology of the porphyrias. 

Treatment During acute porphyria attacks, patients require medical support, particularly treatment for pain and vomiting. The severity of symptoms of the porphyrias can be diminished by intravenous injection of hemin, which decreases the synthe sis of ALA synthase. Avoidance of sunlight and ingestion of j P-carotene (a free-radical scavenger) are also helpful. 

The porphyrias. The human body does not use all of the porphobilinogen produced, and a small amount is normally excreted in the urine, principally as coproporpyrins (Fig. 16-5). In a number of hereditary and acquired conditions blood porphyrin levels are elevated and enhanced urinary excretion (porphy-... 

The porphyrias are a heterogeneous group of inherited disorders of haem biosynthesis. Figure A9.1 shows the pathway of haem synthesis. A deficiency in one of the enzymes results in a specific porphyria. 

This diminishes the HOMO-LUMO gap from the porphyrin, to the chlorin and to the bacteriochlorin, explaining the bathochromic shift of the bands. The oxidation and reduction potentials of these species follow the energy changes of the HOMO and LUMO, respectively. Thus, again within a homologous series, the reduction potentials of the porphyria, chlorin, and bacteriochlorin remain essentially the same, whereas the oxidation potentials become increasingly more facile, with... 

Elder GH. Genetic defects in the porphyrias types and significance. Clin. Dermatol. 1998 16 225-233. 

Inherited factors that influence response to drugs are discussed in general under Pharmacogenetics (p. 122). It is convenient here to describe the porphyrias, a specific group of disorders for which careful prescribing is vital. 

Use of a drug about which there is uncertainty may be justified. Dr M. Badminton writes Essential treatment should never be withheld, especially for a condition that is serious or hfe-threatening. The clinician should assess the severity of the condition and the activity of the porphyria. If no recognised safe option is available, a reasonable course is to ... 

Primary porphyrias are caused by hereditary enzyme defects in haem synthesis. They can be differentiated clinically into acute and chronic porphyrias as well as pathogenetically into hepatic and erythropoietic porphyrias. Secondary porphyrias are symptomatic porphyrias present in various diseases or caused by poisoning or chemical substances, particularly alcohol. Depending on the preferred manifestation site of the enzyme defect, either in the hepatocytes or erythrocytes (bone marrow), the porphyrias are subdivided into hepatic, erythropoietic and hepatoerythropoietic forms. However, this classification is not always strictly applicable. Based on the course of disease, acute and chronic forms may be differentiated in primary hepatic porphyrias. The acute form is characterized by a congenital reg-... 

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