Porphyria are a large group of hereditary diseases characterized by a violation of heme biosynthesis and the accumulation of its toxic metabolites. Clinical manifestations are extremely diverse – from photosensitivity and skin rashes to abdominal pain, complete paralysis and acute psychosis. Diagnostics is carried out using molecular genetic tests, special laboratory methods for determining porphyrins and their precursors in urine and feces, and evaluating the activity of enzymes in the blood. Treatment consists of measures aimed at reducing the formation of toxic metabolites, their removal from the blood, symptomatic therapy and surgical interventions.
ICD 10
E80 E80.0 E80.1 E80.2
General information
Porphyria (from Greek. “porphyreis” – purple) is a number of metabolic diseases in which heme formation is disrupted, as a result of which porphyrins or their toxic precursors accumulate in the body. Pathologies of this group are relatively rare ‒ from 7 to 12 cases per 100,000 people. Individual nosologies have their own endemicity. Thus, the prevalence of late cutaneous porphyria in South African countries is 1:800, acute intermittent porphyria in Sweden is 1:1000, variegate porphyria in South Africa is 1:3000. Most porphyria have no gender differences, except for the late cutaneous form (men are more likely to suffer) and acute intermittent (women are more likely to suffer).
Causes
In the vast majority of cases, the cause of porphyria are genetic mutations that cause the inferiority of the activity of an enzyme involved in heme biosynthesis. The exception is late cutaneous porphyria (sporadic form), which develops due to liver diseases (alcoholic hepatitis, viral hepatitis C) or prolonged intoxication with heavy metals. Porphyria are inherited according to an autosomal dominant or autosomal recessive type. Heme synthesis proceeds in 8 consecutive stages, each is responsible for its own enzyme encoded by a specific gene. There is a specific enzymatic defect for each form of porphyria.
Heme is a complex compound of porphyrins with divalent iron. The largest amount of heme is formed in the liver and bone marrow. In the liver, heme is part of proteins involved in cellular respiration, the breakdown of toxic free radicals and the neutralization of various xenobiotics. In the bone marrow, heme is used to form hemoglobin. The result of reduced enzyme activity is inhibition of heme synthesis at a certain level, which leads to the accumulation of its toxic intermediate metabolites.
In addition to genetic mutation, the development of acute porphyria requires the influence of provoking factors that stimulate the production of porphyrins. Such factors are starvation, prolonged insolation, stress, alcohol, infections, intoxication with heavy metals (mercury, lead), drugs that are metabolized by the cytochrome P-450 system (nonsteroidal anti-inflammatory drugs, antibiotics, anticonvulsants, oral contraceptives, sedatives). Fluctuations of female sex hormones during menstruation or pregnancy play a special role. In women, menstruation is the most frequent provoking factor, and pregnancy is associated with a severe course of the disease.
Pathogenesis
As a result of the inferiority of the enzymes involved in the formation of heme, and the action of provoking factors, an increase in the concentration of its toxic metabolic products occurs. Chronic porphyria are characterized by the accumulation of protoporphyrin, coproporphyrin and upoporphyrin. In acute forms, the amount of porphobilinogen and delta-aminolevulinic acid (DALA) increases.
Porphyrins accumulate in the skin and under the influence of ultraviolet radiation (sunlight) trigger the process of lipid peroxidation, causing the destruction and death of skin cells. Coproporphyrin and protoporphyrin enhance skin pigmentation and accelerate hair growth (hypertrichosis). Poorly soluble in water, protoporphyrin is deposited in liver cells, clogs the portal tracts and bile ducts. The deposition of uroporphyrin in erythrocytes leads to their accelerated destruction in the spleen (hemolysis). Porphyrin precursors (DALA and porphobilinogen), accumulating in the nervous tissue, cause demyelination and axonal degeneration of nerve fibers.
Classification
Different classifications of porphyria are based on different criteria: clinical symptoms, localization of porphyrin metabolism disorders or tissue tropicity. It is most advisable to distinguish the following types of porphyria:
- Erythropoietic. These include congenital erythropoietic porphyria (CEP, Gunther’s disease), erythropoietic protoporphyria (EPP). The main clinical sign is the lesion of skin areas that are exposed to direct sunlight (photosensitization). These pathologies are the most severe and have the highest mortality rate.
- Acute hepatic. This includes acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP). Acute porphyria are characterized by a paroxysmal course. The nervous system mainly suffers. There are also signs of photosensitization with VP and HCP.
- Chronic hepatic. These include late cutaneous porphyria (LCP), which has hereditary and acquired forms. This is the most favorable type of porphyria.
Porphyria symptoms
The range of clinical manifestations is very wide. Porphyria can occur in the form of acute attacks or chronically. Differences are also observed at the age of onset of the disease. Thus, erythropoietic porphyria manifest already in preschool childhood (3-5 years), acute porphyria – after puberty (14-16 years), and sporadic (acquired) form of PCP – after 40 years.
With acute porphyria, severe abdominal pain develops, stool retention, palpitations, increased blood pressure, urine color change (from pink to red-brown). The severity of the patient’s condition is mainly due to neurological symptoms – pain throughout the body, decreased sensitivity, progressive muscle weakness, sometimes reaching complete paralysis, convulsive seizures, various mental disorders (anxiety, psychomotor agitation, delirium, hallucinations).
With a late cutaneous form, hyperpigmentation of skin areas exposed to constant sunlight occurs (face, neck, auricles, upper chest, hands). The skin acquires an earthy or bronze hue. Hypertrichosis of the frontal-temporal region of the face, photosensitization, manifested by increased vulnerability of the skin and the formation of bubbles with liquid contents, are also characteristic. After the bubbles are opened, erosions form. Atrophic scars are formed at the sites of erosion resolution.
With erythropoietic porphyria, there are more pronounced signs of photosensitivity than with LCP (vulnerability, blisters, erosion). With prolonged exposure to the light, redness and severe burning of the skin appear. Extensive erosions leave behind rough scars on the face, which leads to disfigurement of the patient’s appearance. As a result of multiple scars on the skin of the hands, joint contractures develop, which significantly complicates their movements. Urine turns red or pink, and teeth turn red-brown (erythrodontia). Due to an enlarged spleen, heaviness or aching pains in the left hypochondrium may appear. A specific sign of EPP is thickening, coarsening and compaction of the skin around the mouth and eyes, on the wings and back of the nose, on the back surfaces of the hands.
Complications
Violations of porphyrin metabolism worsen the course of cardiovascular diseases, adversely affect carbohydrate metabolism and increase the risk of developing type 2 diabetes. Acute forms of porphyria due to severe polyneuropathy are complicated by paralysis of the respiratory muscles, aspiration pneumonia, cerebral edema, thromboembolism, rhabdomyolysis. Permanent erosion of the skin can lead to bacterial infections. With EPP, liver cirrhosis and liver failure may develop due to the deposition of protoporphyrin insoluble in water.
Diagnostics
If porphyria is suspected, the patient is referred to a hematologist. When making a diagnosis, the presence of the disease in close relatives, the age of the patient, the circumstances of the occurrence of symptoms (insolation, taking medications or alcohol, fasting, infections, menstruation, pregnancy) are taken into account. Laboratory diagnostics of porphyria is as follows:
- Clinical and biochemical analyses. In Gunther’s disease, general and biochemical blood tests reveal signs of hemolysis (poikilocytosis, anisocytosis, spherocytosis, reticulocytosis, an increase in indirect bilirubin and serum iron), an increase in hepatic transaminases. In patients with acute porphyria, there is a decrease in glucose and sodium levels, with LCP – an increase in serum iron and ferritin. Also, 80% of patients with PCP have positive markers of hepatitis C virus.
- Specific studies. For the diagnosis of acute porphyria, the Ehrlich screening test is widely used (when mixing a special reagent with urine, it turns red). AIP is characterized by an increase in DALA and porphobilinogen in urine, for VP – protoporphyrin in feces, for NP – coproporphyrin in feces and urine. With LCP, the content of uroporphyrin in the urine is increased, and coproporphyrin in the feces. With EPP, there is a high concentration of protoporphyrin in erythrocytes and feces, with CEP – uroporphyrin in urine, feces and erythrocytes. With luminescent microscopy, plasma gives red fluorescence in LCP and erythropoietic porphyria.
Also, to confirm the diagnosis, the level of enzymes of the heme biosynthesis cycle in erythrocytes, lymphocytes or plasma is determined – porphobilinogen deaminase (PD), coproporphyrinogen oxidase (CPO), protoporphyrinogen oxidase (VP), uroporphyrinogen synthetase (UPS), uroporphyrinogen decarboxylase (UPD), ferrochelatase (FC). The final stage of diagnosis is molecular genetic testing to detect mutations of genes encoding the enzymes listed above. These studies are particularly effective for recognizing asymptomatic forms of porphyria.
Erythropoietic porphyria differentiate with dermatological diseases (bullous pemphigoid, vulgar pemphigus), with hematological pathologies occurring with splenomegaly (leukemia, lymphoma, autoimmune hemolytic anemia) with kidney diseases. UPD is differentiated with liver diseases, hemochromatosis, adrenal insufficiency. Acute porphyria should be differentiated from surgical diseases accompanied by severe abdominal pain, neurological and psychiatric pathologies.
Treatment
Patients with acute and erythropoietic porphyria should be hospitalized in the hematology department. Treatment of PCP is possible both in the hospital and on an outpatient basis. To date, there are no effective methods that completely eliminate violations of porphyrin metabolism. The main emphasis is on pathogenetic and symptomatic therapy, as well as on the elimination of provoking factors. The methods of treatment depend on the type of porphyria:
- Sharp. To suppress the formation of porphobilinogen and DALA, heme-arginate, ATP derivatives (adenyl, riboxin) and large doses of glucose are used with a further transition to a high-carbohydrate diet. Octreotide is used to relieve vegetative symptoms, and group B vitamins are used to accelerate the recovery of myelin in nerve fibers. Ovariosuppressive therapy is effective in menstrual-dependent attacks. For this purpose, gonadotropin-releasing hormone agonists are prescribed.
- Erythropoietic. These porphyria are very difficult to treat. The main treatment is the protection of the skin from sunlight (windows with glass that does not pass ultraviolet light, closed clothing, photoprotective creams, beta–carotene intake). It is necessary to treat erosions with antiseptic solutions to prevent infectious complications. Splenectomy is indicated for severe hemolysis. In some cases of Gunther’s disease, bone marrow transplantation is effective. With EPP, hepatoprotectors (ursodeoxycholic acid, ademethionine) and anti-cirrhotic therapy are additionally prescribed.
- PKP. In order to remove porphyrins and excess iron, plasmapheresis and phlebotomy (bloodletting) are performed. With contraindications to these procedures, aminoquinoline (chloroquine) and complexing (deferoxamine) drugs are prescribed. Enterosorbents (activated charcoal) are used to reduce the absorption of porphyrins in the gastrointestinal tract. Sunscreens are also used. In the presence of hepatitis C, antiviral therapy with interferon-alpha and ribavirin is necessary.
Prognosis and prevention
In most cases, porphyria are severe diseases with an unfavorable prognosis. With erythropoietic forms, life expectancy is about 30 years, death occurs from intercurrent infections. EPP often leads to cirrhosis of the liver. With attacks of acute porphyria, the lethal outcome is observed in 15-20%, the main cause of death is paralysis of the respiratory muscles. With PKP, the prognosis is favorable, severe complications do not occur. To prevent relapses, it is recommended to avoid provoking factors – infections, starvation, stress, prolonged exposure, alcohol consumption and certain medications. People who have a porphyria patient in their family need to determine the activity of enzymes in the heme synthesis cycle and conduct DNA diagnostics to identify genetic mutations.
