Porphyrias

The porphyrias are a group of rare disorders that affect heme biosynthesis (the formation of chemical compounds by living organisms). Heme is an essentialcomponent of hemoglobin (the iron-containing pigment of the blood that carries oxygen from the lungs to the tissues) as well as many enzymes throughout the body. Biosynthesis of heme is a process that starts with simple moleculesand ends with a large, complex heme molecule. Each step of the biosynthesis pathway is directed by its own protein, called an enzyme. As a heme precursormolecule moves through each step, an enzyme modifies it in some way. If the precursor is not modified, it cannot proceed to the next step.

Due to a defect in one of the enzymes of the heme biosynthesis pathway, protoporphyrins or porphyrin (heme precursors) are prevented from proceeding further along the pathway. Instead, precursors accumulate at the stage of the enzyme defect and cause a variety of physical symptoms in the affected person. Specific symptoms depend on the point at which heme biosynthesis is blocked andwhich precursors accumulate. In general, the porphyrias primarily affect theskin and the nervous system. Symptoms can be debilitating or life threatening in some cases. Porphyria is an inherited condition, but it may be acquiredafter exposure to poisonous substances.

Heme is produced in several tissues in the body, but its main biosynthesis sites are the liver and the bone marrow. Although production is concentrated inthe liver and bone marrow, heme is used in nearly every tissue in the body.In most cells, it is a key building block in the construction of factors thatoversee metabolism as well as transport of oxygen and energy. In the liver,heme is used in several vital enzymes, particularly one that is involved in the metabolism of chemicals, vitamins, fatty acids, and hormones. It is very important in transforming toxic substances into easily excretable materials. In immature red blood cells, heme is a the major component of hemoglobin

The production of heme may be compared to a factory assembly line. At the start of the line, raw materials are fed into the process. At specific points along the line, an addition or adjustment is made to further development. Onceadditions and adjustments are complete, the final product roles off the end of the line.

The control of heme biosynthesis is complex. There are various chemical signals that can trigger increased or decreased production. These signals can affect the enzymes themselves or their production, starting at the genetic level.Under normal circumstances, when heme concentrations are at an appropriate level, precursor production decreases. However, a glitch in the biosynthesis pathway represented by a defective enzyme means that heme biosynthesis is incomplete. Because heme levels remain low, the synthesis pathway continues to churn out precursor molecules in an attempt to make up the deficit.

The net effect of this continued production is an abnormal accumulation of precursor molecules and development of some type of porphyria. Each type of porphyria corresponds with a specific enzyme defect and an accumulation of the associated precursor.

The porphyrias are divided into two general categories, depending on the location of the deficient enzyme. Porphyrias that affect heme biosynthesis in theliver are called hepatic porphyrias. The porphyrias that affect heme biosynthesis in immature red blood cells are called erythropoietic porphyrias (erythropoiesis is the process through which red blood cells are produced).

Enzymes involved in heme biosynthesis have subtle, tissue-specific variations; therefore, heme biosynthesis may be impeded in the liver, but normal in theimmature red blood cells, or vice versa. Incidence of porphyria varies widely between types and occasionally by geographic location. Although certain porphyrias are more common than others, their greater frequency is only relativeto other types. All porphyrias are considered rare disorders.

The underlying cause of all porphyrias is a defective enzyme somewhere alongthe heme biosynthesis pathway. In nearly all cases, the defective enzyme is agenetically linked factor. Therefore, porphyrias are inheritable conditions.However, an environmental trigger such as diet, drugs, or sun exposure may be necessary before any symptoms develop. In many cases, symptoms do not develop, and people may be completely unaware that they have a gene for porphyria.

Nearly all of the hepatic porphyrias follow a pattern of acute attacks interspersed among periods of complete symptom remission. For this reason, they areoften referred to as the acute porphyrias. The erythropoietic porphyrias donot follow the same pattern and are considered chronic conditions.

The specific symptoms of each porphyria depend on the affected enzyme and whether it occurs in the liver or in the bone marrow. The severity of symptoms can vary widely, even within the same porphyria type. If the porphyria becomessymptomatic, the common factor between all types is an abnormal accumulationof protoporphyrins or porphyrin.

Depending on the symptoms presented, the possibility of porphyria may not immediately come to mind. In the absence of a family history of porphyria, somesymptoms of porphyria, such as abdominal pain and vomiting, may be attributedto other disorders. Neurological symptoms, including confusion and hallucinations, can lead to an initial suspicion of psychiatric disease rather than aphysical disorder. Diagnosis may be aided in cases in which these symptoms appear in combination with neuropathy (any disease of the nerves), sensitivityto sunlight, or other factors. Certain symptoms, such as urine the color of port wine, are hallmark signs of porphyria.

A common initial test measures protoporphyrins in the urine. However, if skinsensitivity to light is a symptom, a blood plasma test is indicated. If these tests reveal abnormal levels of protoporphyrins, further tests are done tomeasure heme precursor levels in the stool and in red blood cells.Whether heme precursors occur in the blood, urine, or stool gives some indication of thetype of porphyria, but more detailed biochemical testing is required to determine their exact identity. Making this determination yields a strong indicator of which enzyme in the heme biosynthesis pathway is defective, which, in turn, allows a diagnosis of the particular type of porphyria.

Biochemical tests rely on the color, chemical properties, and other unique features of each heme precursor. Other biochemical tests rely on the fact thatheme precursors become less water soluble (able to be dissolved in water) asthey progress further through the heme biosynthesis pathway. As a final test,measuring specific enzymes and their activities may be done for some types of porphyrias.

Treatment for porphyria revolves around avoiding acute attacks, limiting potential effects, and treating symptoms. However, treatment options vary depending on the type of porphyria that has been diagnosed.

A person who has been diagnosed with, for example, intermittent porphyria, can prevent most attacks by avoiding precipitating factors, such as certain drugs that have been identified as triggers for acute porphyria attacks. Individuals must maintain adequate nutrition, particularly with respect to carbohydrates. In some cases, an attack can be stopped by increasing carbohydrate consumption or by receiving carbohydrates intravenously.

If an attack occurs, medical attention is needed. Pain is usually severe, andnarcotic analgesics are the best option for relief. Medications can be usedto counter nausea, vomiting, and anxiety as well as for sedation or to inducesleep. An intravenously administered drug called hematin may be used to curtail an attack. Women, who tend to develop symptoms more frequently than men owing to hormonal fluctuations, may find hormone therapy that inhibits ovulation to be helpful.

Acute porphyria attacks can be life-threatening events, so it is not advisable to try self-treatments in these situations. Alternative treatments can be useful adjuncts to conventional therapy. For example, some people may find relief for the pain associated with some porphyrias through acupuncture or hypnosis. Relaxation techniques, such as yoga or meditation, may also prove helpful in pain management.

Even in the presence of a genetic inheritance for a porphyria, symptom development depends on a variety of factors. In the majority of cases, a person remains asymptomatic throughout life. Porphyria symptoms are rarely fatal with proper medical treatment, but they may be associated with temporarily debilitating or permanently disfiguring consequences. Measures to avoid these consequences are not always successful, regardless of how diligently they are pursued. Although pregnancy has been known to trigger porphyria attacks, it is notas great a danger as was once thought.

If there is a family history of porphyria, a person should consider being tested to determine whether he or she carries the associated gene. Even if symptoms are absent, it is useful to know about the presence of the gene to assessthe risks of developing the associated porphyria. This knowledge also reveals whether a person's offspring may be at risk. Theoretically, it is possibleto do prenatal tests. However, these tests would not indicate whether the child would develop porphyria symptoms; only that they might have the potentialto do so.

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