Target Health Blog

Porphyria

July 20, 2020

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Urine of patient with porphyria: Change in urine color before and after sun exposure. Left figure is urine of the first day. Right figure is urine after sun exposure for 3 days. Urine color changed to “port wine“ color after sun exposure. This color change is due to increased concentrations of porphyrin intermediates in the urine, indicating an abnormality in production and a partial block within the enzymatic porphyrin chain with metabolite formation. The urine color usually becomes darker with acute illness, even dark reddish or brown after sun exposure.
Photo credit: by Chen GL, Yang DH, Wu JY, Kuo CW, Hsu WH - Neuropathic pain in hereditary coproporphyria. Chen GL, Yang DH, Wu JY, Kuo CW, Hsu WH - Pak J Med Sci (2013)
https://openi.nlm.nih.gov/detailedresult.php?img=PMC3809238_pjms-29-672-g001&query=porphyria&req=4&npos=30, CC BY 3.0; Wikipedia Commons

Porphyria is a group of mostly genetic diseases in which substances called 1) _____ build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and short in duration. Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. The attacks usually last for days to weeks. Complications may include paralysis, low blood sodium levels, and seizures. Attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications. If the skin is affected, blisters or itching may occur with sunlight exposure.

Most types of porphyria are inherited from one or both of a person's parents and are due to a mutation in one of the genes that make 2) _____. They may be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant manner. One type, porphyria cutanea tarda, may also be due to increased iron in the liver, hepatitis C, alcohol, or HIV/AIDS. The underlying mechanism results in a decrease in the amount of heme produced and a build-up of substances involved in making heme. Porphyrias may also be classified by whether the liver or bone marrow is affected. Diagnosis is typically made by blood, urine, and stool tests. Genetic testing may be done to determine the specific 3) _____.

Treatment depends on the type of porphyria and the person's symptoms. Treatment of porphyria of the skin generally involves the avoidance of sunlight, while treatment for acute porphyria may involve giving intravenous heme or a glucose solution. Rarely, a liver transplant may be carried out. The precise prevalence of porphyria is unclear, but it is estimated to affect between 1 and 100 per 50,000 people. Porphyria cutanea tarda is believed to be the most common type. The disease was described as early as 370 BCE by 4) _____. The underlying mechanism was first described by German physiologist and chemist Felix Hoppe-Seyler in 1871. The name porphyria is from the Greek porphyra, meaning "purple", a reference to the color of the urine that may be present during an attack.

The acute porphyrias are acute intermittent porphyria (AIP), variegate porphyria (VP), aminolevulinic acid dehydratase deficiency porphyria (ALAD) and hereditary coproporphyria (HCP). These diseases primarily affect the nervous system, resulting in episodic crises known as acute attacks. The major symptom of an acute attack is abdominal pain, often accompanied by vomiting, hypertension (elevated blood pressure), and tachycardia (an abnormally rapid heart rate). The most severe episodes may involve neurological complications: typically motor neuropathy (severe dysfunction of the peripheral nerves that innervate muscle), which leads to muscle weakness and potentially to quadriplegia (paralysis of all four limbs) and central nervous system symptoms such as seizures and coma. Occasionally, there may be short-lived psychiatric symptoms such as anxiety, confusion, hallucinations, and, very rarely, overt psychosis. All these symptoms resolve once the acute attack passes.

Given the many presentations and the relatively low occurrence of porphyria, patients may initially be suspected to have other, unrelated conditions. For instance, the polyneuropathy of acute porphyria may be mistaken for 5) _____ _____ syndrome, and porphyria testing is commonly recommended in those situations. The non-acute porphyrias are X-linked dominant protoporphyria (XLDPP), congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP). None of these are associated with acute attacks; their primary manifestation is with skin disease. For this reason, these four porphyrias - along with two acute porphyrias, VP and HCP, that may also involve skin manifestations - are sometimes called cutaneous porphyrias.

Two distinct patterns of skin disease are seen in porphyria:

Immediate photosensitivity. This is typical of XLDPP and EPP. Following a variable period of sun exposure - typically about 30 minutes - patients complain of severe pain, burning, and discomfort in exposed areas. Typically, the effects are not visible, though occasionally there may be some redness and swelling of the skin.

Vesiculo-erosive skin disease. This characteristic blistering (vesicles) and open sores (erosions) noted in patients is the pattern seen in CEP, PCT, VP, and HCP. The changes are noted only in sun-exposed areas such as the face and back of the hands. Milder skin disease, such as that seen in VP and HCP, consists of increased skin fragility in exposed areas with a tendency to form blisters and erosions, particularly after minor knocks or scrapes. These heal slowly, often leaving small scars that may be lighter or darker than normal skin. More severe skin disease is sometimes seen in PCT, with prominent lesions, darkening of exposed skin such as the face, and hypertrichosis: abnormal 6) _____ _____ on the face, particularly the cheeks. The most severe disease is seen in CEP and a rare variant of PCT known as hepatoerythropoietic porphyria (HEP); symptoms include severe shortening of digits, loss of skin appendages such as hair and nails, and severe scarring of the skin with progressive disappearance of ears, lips, and nose. Patients may also show deformed, discolored teeth or gum and eye abnormalities.

Cause

The porphyrias are generally considered genetic in nature. Subtypes of porphyrias depend on which enzyme is deficient. In the autosomal recessive types, if a person inherits a single gene, they may become a carriers. Generally they do not have symptoms, but may pass the gene onto offspring.

Triggers

Acute porphyria can be triggered by a number of drugs, most of which are believed to trigger it by interacting with enzymes in the liver which are made with heme. Such drugs include: Sulfonamides, including sulfadiazine, sulfasalazine and trimethoprim/sulfamethoxazole; Sulfonylureas like glibenclamide, gliclazide and glimepiride, although glipizide is thought to be safe; Barbiturates including thiopental, phenobarbital, primidone, etc.

Pathogenesis

In humans, porphyrins are the main precursors of heme, an essential constituent of 7) _____, myoglobin, catalase, peroxidase, and P450 liver cytochromes. The body requires porphyrins to produce heme, which is used to carry oxygen in the blood among other things, but in the porphyrias there is a deficiency (inherited or acquired) of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. Porphyrias are classified in two ways, by symptoms and by pathophysiology. Physiologically, porphyrias are classified as liver or erythropoietic based on the sites of accumulation of heme precursors, either in the liver or in the bone marrow and red blood cells.

There are eight enzymes in the heme biosynthetic pathway, four of which?the first one and the last three?are in the 8) _____, while the other four are in the cytosol. Defects in any of these can lead to some form of porphyria.

Diagnosis

Porphyria is diagnosed through biochemical analysis of blood, urine, and stool. In general, urine estimation of porphobilinogen (PBG) is the first step if acute porphyria is suspected. As a result of feedback, the decreased production of heme leads to increased production of precursors, PBG being one of the first substances in the porphyrin synthesis pathway. In nearly all cases of acute porphyria syndromes, urinary PBG is markedly elevated except for the very rare ALA dehydratase deficiency or in patients with symptoms due to hereditary tyrosinemia type I. In cases of mercury- or arsenic poisoning-induced porphyria, other changes in porphyrin profiles appear, most notably elevations of uroporphyrins I & III, coproporphyrins I & III, and pre-coproporphyrin.

Repeat testing during an attack and subsequent attacks may be necessary in order to detect a porphyria, as levels may be normal or near-normal between attacks. The urine screening test has been known to fail in the initial stages of a severe, life-threatening attack of acute intermittent porphyria.[citation needed]

Up to 90% of the genetic carriers of the more common, dominantly inherited acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been noted in DNA tests to be latent for classic symptoms and may require DNA or enzyme testing. The exception to this may be latent post-puberty genetic carriers of hereditary coproporphyria.

As most porphyrias are 9) _____ conditions, general hospital labs typically do not have the expertise, technology, or staff time to perform porphyria testing. In general, testing involves sending samples of blood, stool, and urine to a reference laboratory. All samples to detect porphyrins must be handled properly. Samples should be taken during an acute attack; otherwise a false negative result may occur. Samples must be protected from light and either refrigerated or preserved.

If all the porphyrin studies are negative, one must consider 10) _____. A careful medication review often will find the cause of pseudoporphyria.

ANSWERS: 1) porphyrins; 2) heme; 3) mutation; 4) Hippocrates; 5) Guillain-Barre; 6) hair growth; 7) hemoglobin; 8) mitochondria; 9) rare; 10) pseudoporphyria

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