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A Guide To Porphyria

How is porphyria diagnosed?
The diagnosis of porphyria is often difficult to make, in part due to the fact that the symptoms can mimic many other clinical states and the fact that the disease is sufficiently rare that most doctors have very limited personal experience with it. The recollection that some other member of the family, even a distant cousin, had this problem is often the key to the diagnosis. Since the multiple disease syndromes known as porphyria are all due to defective enzyme functions, there are abnormal accumulations of a variety of compounds involved in the metabolic pathway. Some of these are water soluble and so are freely excreted in the urine, others are found in feces after being metabolized by the liver and excreted into the bile. The classic laboratory finding that is described is the demonstration of red urine, either immediately on being passed or after standing in bright sun light. This is due either to the excretion of preformed porphyrin molecules or possibly by the nonenzymatic condensation of the high concentration of PBG into tetrapyrrole porphyrin molecules.

Ideally, the laboratory diagnosis of porphyria should be based on either the identification of the DNA structure of the defective gene or the measurement of the activity of the specific enzyme system that is affected. These procedures are not as yet available on a routine basis. As a result, the laboratory diagnosis still depends primarily on the tests which will identify abnormal concentrations of either the precursors of porphyrins or the porphyrins themselves or both. The compounds which are usually measured include PBG, ALA, uroporphyrin and coproporphyrin, and they are found in the urine, feces, plasma and red blood cells. When the diagnosis of porphyria is considered clinically, the initial screening test should be the determination of the concentration of PBG and ALA in a random sample of urine. Porphobilinogen production is elevated in AIP, VP, and HCP. There are several procedures used for these tests and most laboratories have upgraded their protocols to use the newest techniques in order to make the screening tests more specific and sensitive. The diagnostic tests for urinary PBG, ALA and porphyrin excretion are done on a 24 hour collections of urine and require specific preservatives. The urine should be collected in an opaque bottle and refrigerated to prevent the breakdown of the compounds. These tests are often difficult for the patient to complete as the urine must be collected and stored under very specific conditions and not all laboratories can do these tests. Although a sick patient will usually cooperate with the instructions for collection and storage of a 24 hour urine sample, many asymptomatic possible carriers of the gene who are being screened will not bother. In addition, the results are often not a true reflection of the changing metabolic state of the patient, they may be technically unreliable and are often difficult to interpret when they are borderline positive.

It is essential that before arranging for these tests, the doctor consult with the laboratory to ensure that the tests are available and also know the recommended procedures as to how and when to collect the blood, stool and urine samples. In addition, there is considerable overlap of the laboratory results between the various diseases, which complicates the difficulties of making a specific diagnosis. It can be very difficult to identify the patients with latent disease, particularly youngsters before the age of puberty. Some specialized university based referral laboratories will make other tests available using more sophisticated techniques. The activity of the enzyme porphobilinogen deaminase which is deficient in patients with AIP can be measured in their red blood cells and is available in some reference laboratories. In addition the technique of high performance liquid chromatography can be used to accurately measure the concentrations of porphyrins in the urine, stool and plasma samples.

Is porphyria treatable?
Simply put, the answer is yes. Prevention of the acute attacks in both known sufferers of the disease and suspected latent carriers is the most important approach. In a known porphyric patient it is essential to identify the factors that can precipitate the acute symptoms. The avoidance of porphyrogenic medications, bright sunlight or alcohol is often all that is necessary to avoid these attacks. In women with repeated premenstrual relapses, the inhibition of ovulation by the use of pituitary hormones or the LHRH analogues such as leuprolide may be effective in reducing their frequency. High carbohydrate diets are also helpful.

During the acute attacks, supportive therapy is required including narcotic analgesics, tranquilizers such as chlorpromazine, antinauseants, rehydration, sodium and magnesium replacement, high carbohydrate diets and sometimes intravenous therapy with high concentrations of glucose. Hematin and heme arginate, which are essentially the final products of the heme biosynthetic pathway can be given intravenously and act as specific agents to treat several types of porphyria by decreasing the activity of the enzyme ALA synthase, the first step in the heme biosynthetic cascade. The reduced activity of this enzyme slows down the entire metabolic pathway and stops the overproduction of ALA and PBG. However this drug must be used with caution as it can be associated with side effects.

During severe attacks the patient may on occasion require hospitalization. Seizures are often a difficult problem to control since many of the drugs used to control epilepsy such as Dilantin may precipitate or worsen attacks of porphyria. The anticonvulsant gabapentin has been shown to be effective and safe. Each type of porphyria has its own specific therapeutic program and it is important to try to identify the specific enzyme defect if possible. In cases of iron overload or lead toxicity the removal of the offending heavy metal excess may be all that is required. There appears to be some evidence that the treatment of hepatitis C with interferon and ribaviron may also be effective.

There are several drugs and medications used to treat other diseases that can precipitate an acute attack, but there are many more that are safe. It is preferable to take only the medicines that are absolutely essential. Before the patient with porphyria takes any drug they must ensure its safety. This is often difficult because of the limited experience of doctors, pharmacists and even university clinics in this field. If possible the family should check with the drug manufacturer or distributor about its porphyrogenic properties and history. The drug companies usually keep records of drug side effects. Most pharmaceutical houses have toll free phone numbers and are able to provide this information readily by fax or telephone. It is also important that the patients and the doctors share their knowledge and experience as widely as possible.

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