Porphyria

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Classification according to ICD-10
E80 Disorders of the porphyrin and bilirubin metabolism
ICD-10 online (WHO version 2019)

Among the porphyria ( ancient Greek πορφυρία porphyria , derived from ancient Greek πορφυρά Porphyra , purple ') refers to a group of (usually congenital) metabolic diseases associated with a disturbance of the formation of hemoglobin heme associated. The enzymes involved in haem biosynthesis - depending on which of the eight enzymes has a defect, specific intermediate products of haem synthesis accumulate in the various organs and cause the symptoms typical for the respective porphyria .

Forms of porphyria

There are seven types of genetically determined porphyrias: The heme group (the red blood pigment) is built up in eight steps from simple precursors, each step is catalyzed by a specific enzyme . Depending on which of the enzymes shows restricted activity, another metabolic product accumulates and causes the respective symptoms. The types of porphyria are divided into two groups based on their main symptoms, but between which the symptoms overlap.

The acute or acute hepatic porphyrias are accompanied by attacks of sudden severe abdominal pain, depending on the disease and severity, liver problems and neurological deficits occur. Acute porphyria (Latin Porphyria acuta ) was formerly known as Porphyria hepatica . Cutaneous porphyrias show a painful sensitivity to light, and the liver can also be affected. Another differentiation of porphyrias into erythropoietic (affecting the formation of red blood cells) and hepatic (affecting the liver) forms relates to the location of the heme formation, where the enzyme deficiency causes most problems.

Erythropoietic porphyrias:

Hepatic porphyrias:

The Orthomolecular medicine claims that the Hämopyrrollaktamurie , also called pyrroluria or kryptopyrroluria to have discovered, however, for whose existence no evidence exist. Hemopyrrollactamuria is said to have more psychological symptoms than the other forms.

Acquired porphyries

Poisoning z. B. with lead, mercury or certain pesticides damage enzymes of the heme biosynthesis and cause the same symptoms as the respective genetic porphyria.

Symptoms

Acute porphyrias

Characteristic is the intermittent course, acute crises with severe abdominal pain and sometimes light intolerance reactions (depending on the type of porphyria) alternate with often long asymptomatic phases. Acute porphyrias (also called porphyria acuta ) include AIP, PV, HCP and ALAD deficiency porphyria .

The following symptoms can, but need not all, occur during an acute attack:

Attacks are triggered by drugs ( see below ), many types of chemical substances, hormones (menstruation, “ pill ”, stress), hunger and other factors.

The problem, especially in undiagnosed cases, is that many drugs are not tolerated and lead to a worsening of the patient's condition (drugs activate the body's own detoxification system and lead to increased heme group synthesis, which increases the amount of heme intermediates and thus symptoms worsen).

A list of drugs classified as safe can be found on the homepage of the European Porphyria Initiative EPI.

Since many cases of porphyria are not recognized (no morphological changes in the abdominal tract) and neuropsychic deficits can occur, the patients are often classified as mentally ill.

Cutaneous porphyrias

A characteristic of cutaneous (skin-related) porphyrias is the strong, extremely painful light sensitivity of the skin to primarily visible light around 406 nm ( Soret band ), which leads to massive and disfiguring skin and tissue damage. Types of porphyria with intolerance to the sun and light are CEP, HEP, PCT, HCP, PV and EPP.

Symptoms, depending on the type of porphyria:

  • Scarring, tissue death and disfigurement (loss of nose, lips, auricles, finger parts, etc.) (CEP, HEP)
  • Storage of porphyrins ( hemoproteins ) in the teeth ( erythrodontia ) and bones, red autofluorescence (CEP)
  • Blistering of the skin
  • EPP: In the early stages of sun exposure, despite pain, no visible changes to the skin, later (after 12–24 hours) redness and swellings and extensive burns
  • only uncovered areas of the skin are affected
  • pain may start after a few minutes in the sun; only opiates are effective
  • the liver can be damaged by porphyrin deposits up to cirrhosis .

Hereditary porphyrias are rare diseases that usually have a complicated inheritance (skipping several generations, etc.) and are therefore often not recognized; this represents a not inconsiderable risk factor for those affected, as the diseases are extremely painful and potentially life-threatening.

"Dracula symptoms": Erythrodontia ("blood teeth"), photophobia (day sleeper ), anemia (pallor due to a lack of red blood pigment).

"Werewolf symptoms": hypertrichosis (increased facial hair after photodermatosis has healed), erythrodontia ("blood teeth"), nasal and / or fingerlessness (mutilation due to cartilage-bone tissue destruction).

proof

Porphyria is diagnosed by detecting specific porphyrin precursors in blood, urine and / or stool. The various precursors are separated using powerful chromatographic processes ( HPLC ). Porphyrin precursors are normally used immediately by the body, so an increase indicates porphyria. The specific composition of the precursor substances present in increased concentration shows the type of porphyria. Acute porphyrias usually only show increased values ​​in acute attacks. The detection should be carried out by a specialized laboratory.

The urine, which sometimes turns red in the air (only during / before the attacks), provides an indication of some forms of acute porphyria.

An outdated detection method for EPP was the excitation of the unbound protoporphyrin in the blood with certain light wavelengths in order to excite the self-fluorescence of the porphyrin scaffold ( Soret band ).

In most cases, analyzes of the affected gene are carried out in order to assess the risk of the disease for relatives and offspring . If the mutation is found in the patient's gene, the specific gene locus (location) can be very easily tested for the change in the family members. Genetic counseling centers can then provide information about the (sometimes very low) risk of passing it on to children.

therapy

Acute porphyrias

A causal therapy does not yet exist. The risk of a flare-up can be reduced by avoiding triggering substances such as most drugs, alcohol and smoking and by ensuring a regular carbohydrate intake (eating regularly). If new medications have to be taken, the advice of a porphyria specialist should be sought beforehand. It should be noted that information in current compendia is often out of date. Lists of drugs that, according to the current state of knowledge, can be safely used for acute porphyrias can be found on the websites of the porphyria competence centers.

Acute attacks of porphyria can be treated symptomatically by administering high amounts of carbohydrates ( glucose ) or hemin or hemin arginate (hemin, brand name Normosang , should not be confused with hematin ).

Mode of action: The heme group occurs mainly in hemoglobin (red blood pigment), but also in enzymes such as cytochrome P450 , which u. a. plays a role in the breakdown or detoxification of xenobiotics (e.g. drugs) in the liver. Have to increase z. B. drugs are broken down, there is an increased need for cytochrome P450 and a positive feedback on the heme synthesis pathway. If the synthesis pathway is disturbed, however, the heme requirement cannot be met; the positive feedback instead leads to an enrichment of the metabolic product that cannot be converted (further processed) at the normal rate. Since porphyrin precursors are toxic (poisonous) to the body, symptoms of a relapse occur. Hemin arginate occupies the positive feedback point in the synthesis pathway of the heme (it suggests to the body that a sufficient amount of heme is present) and thereby interrupts the relapse-triggering feedback.

Some porphyrias respond to bloodletting therapies, but the anemia is exacerbated.

Riboflavin is also being discussed for the treatment of porphyrias .

Cutaneous porphyrias

A causal therapy does not yet exist, avoiding (sun) light and substances harmful to the liver (alcohol, etc.) is currently the only way to protect against an outbreak of symptoms. Since the wavelengths that trigger symptoms are in the visible range of light Sunscreen useless, as there is only a protective effect in the UV range. The same applies to other materials (protective films, textiles, etc.) with a UV protection factor. However, a derivative of the alpha- MSH hormone is currently in the test phase, which leads to tanning of the skin via hormonal stimulation even without exposure to the sun and which has achieved a high protective effect in preliminary studies.

Chemistry of the porphyrins

Porphyrins are a class of colored molecules (from ancient Greek πορφυρά porphyrá , the purple dye ). The in red blood cells occurring oxygen-transporting protein hemoglobin (red blood color) as a prosthetic group of the heme , an iron (II) - porphyrin consisting of tetrapyrrole is constructed as a base body. An iron ion, which is essential for oxygen binding, is complexed in its center . If the heme synthesis is disturbed, other porphyrins, the namesake of porphyria, are created instead. With these porphyrins no iron ion is anchored in the nitrogen ring. Since heme is also a component of many other proteins such as cytochromes or myoglobin , this central location of the disruption of biosynthesis causes a wealth of different symptoms in porphyria in the various systems: nervous and digestive systems, internal respiration , skin and psyche.

literature

Specialist literature

The first description of porphyria was done by Hans Günther : Die Hematoporphyrie . In: Dtsch. Arch. F. Klin. Med. , 1912, 105, pp. 89-146.

  • Pamela Poblete Gutiérrez, Tonio Wiederholt, Klaus Bolsen, Kerstin Gardlo, Claudia Schnabel, Gerd Steinau, Frank Lammert, Clemens Bartz, Oliver Kunitz, Jorge Frank: Diagnosis and therapy of porphyrias: an interdisciplinary challenge . In: Deutsches Ärzteblatt . tape 101 , no. 18 , April 30, 2004, pp. A-1250 / B-1030 / C-998 .
  • Christine Vetter: Porphyries: Considerable number of unreported cases . In: Deutsches Ärzteblatt . tape 103 , no. 38 , September 22, 2006, pp. A-2446 / B-2121 / C-2045 .
  • Hans Günther: The importance of the hematoporphyrins in physiology and pathology. In: Results of general pathology u. pathological anatomy. 1922. Vol. 20, Abt. 1, pp. 608-764. Munich u. Wiesbaden 1922.
  • Jan Waldenström: Studies on Porphyria. In: Acta med. scand. Stockholm 1937, Suppl. 82.
  • Ida Macalpine, Richard Hunter: The insanity of King George III, a Classic Case of Porphyria. In: British Medical Journal. 1966, pp. 65-71.
  • Ida Macalpine, Richard Hunter, C. Rimington: Porphyria in the Royal Houses of Stuart, Hanover, and Prussia - A Follow-up Study of George III's Illness. In: British Medical Journal. 1968, 1, pp. 7-18.
  • Ida Macalpine, Richard Hunter: Georg III and the Mad Business. Penguin, London 1969.
  • Claus A. Pierach, Erich Jennewein: Friedrich Wilhelm I. and the porphyria. In: Sudhoff's archive. Journal of the History of Science. Volume 83, Number 1, 1999, pp. 50-66.
  • John CG Röhl, Martin Warren, David Hunt: Purple Secret. Genes, Madness' and the Royal Houses of Europe. London 1998 and 1999.

Literary processing

  • Isabel Allende : Paula , Chile 1994 - novel by the writer Isabel Allende about the daughter Paula who suffered from porphyria.

Web links

Individual evidence

  1. ↑ Ludwig Weissbecker: Porphyria and Porphyrinuria. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition ibid. 1961, pp. 1121–1124, here: p. 1123.
  2. ↑ Wolfgang Dorst: Diagnosis and therapy of porphyrias: therapy with riboflavin . In: Deutsches Ärzteblatt . tape 101 , no. 48 . Deutscher Ärzte-Verlag , November 26, 2004, p. A-3275 / B-2777 / C-2631 .