Q: What is porphyria and how is it treated?
A: The types of porphyria (cutaneous or acute) occur because of a defect in one of the heme synthesizing enzymes. The protein heme is made in essentially all body tissues, but primarily in the bone marrow (accounting for about 80%, and used to make hemoglobin, the protein that carries oxygen in red blood cells) and the liver (accounting for almost all the rest and used to make certain liver enzymes). The defect in heme synthetization causes an accumulation of one of the heme precursors (porphyrins); when they acutely build up they can cause toxicity to the nerves and/or skin.
Porphyria may be due to several possible genetic defects. It may be inherited in several different manners, or may be sporadic (occurring due to a spontaneous gene defect, so not inherited). Some are autosomal dominant (one gene from either parent is sufficient to inherit), although this variant often has limited penetrance (the heme buildup is not severe enough to cause symptoms in many patients). Some variants are recessive (the patient must inherit an abnormal gene from each parent) with the severity of symptoms dependent on the specific genetic defect, and some are X-linked (inherited on the sex-linked X chromosome) so a mother can give it to either child (girls are XX and boys are XY so both get an X from mom) while the father can only pass it on to his daughters (their sons get dad’s Y chromosome).
Many people with porphyria never manifest symptoms, but for those that do, symptomatic attacks usually begin in adulthood, typically between ages 20-40. Diagnosis of porphyria is made by screening for excesses of porphyrins during an acute attack. Elevated porphyrins may be found in urine, stool and/or blood. When suspicion of porphyria is high, or there is a positive screening test during an acute attack, further testing is indicated. DNA evaluation may be done to identify the specific genetic defect (including in asymptomatic patients with a strong family history of the condition).
Since porphyria causes only a partial enzyme defect there is often a trigger that causes symptoms to manifest. Common triggers include certain medications, certain chemical exposures, stress, surgery, alcohol, sun exposure, smoking, infections, iron overload and/or many others.
Cutaneous porphyria manifests as skin oversensitivity to light, causing itch, redness and swelling. The most common of these (affecting about 1 in 25,000 Americans) is called porphyria cutanea tarda (PCT) and also causes blistering of the skin. About 80% of PCT cases are ‘sporadic’ (not inherited), with the other 20 percent being autosomal dominant. The less common cutaneous porphyria (erythropoietic protoporphyria) does not cause blistering; it is also autosomal dominant.
Some patients with cutaneous porphyria having ongoing symptoms will benefit from phlebotomy to reduce iron stores; this can help induce a remission. Activated charcoal (to absorb some of the porphyrins) and Vitamin A may also be helpful. Of course these patients should also avoid sun exposure and any other symptom triggers. Cutaneous porphyria can cause long term skin damage.
The most common symptom of acute porphyria is abdominal pain (affecting about 90% of symptomatic patients) due to toxicity to the visceral nerves. The abdominal pain of acute porphyria is typically severe and out of proportion to the physical exam (the patient is not very tender to palpation), crampy in nature and often accompanied by vomiting, constipation and/or distention. When peripheral nerves are affected from acute porphyria the patient may have pain and/or numbness in their arms, legs, chest and/or back. Autonomic nerve involvement can affect blood pressure and/or heart rate. Involvement of the central nervous system can cause seizures, neuropsychiatric symptoms and even electrolyte abnormalities (from affects to certain hormones made in the brain). Many other symptoms, depending on the nerves affected, can occur as well. The most common acute porphyria, acute intermittent porphyria (AIP), is inherited in a dominant fashion and affects about 1 in 200,000 Americans.
Patients with acute porphyria can minimize attacks by avoiding their triggers. During an acute attack they will often need to be hospitalized for treatments such as pain medication, correction of any electrolyte imbalance, intravenous fluids for dehydration, other symptomatic treatments, intravenous glucose and/or injections of hemin or hematin (forms of heme) to decrease their body’s need to make heme. Attacks of acute porphyria can be life threatening. Over time multiple attacks can adversely affect the liver, kidney and possibly other organs.
A new kind of treatment (sometimes called gene silencing) for acute porphyria is under investigation, and is worth discussing since it is an interesting conceptual approach and may be applicable to certain other diseases. A protein is ‘manufactured’ in cells by messenger RNA (mRNA) taking the ‘blueprint’ instruction of how to make it from the patient’s DNA and passing this information to transfer RNA (tRNA), which transfers individual amino acids (the building blocks of proteins) to allow the cell to assemble the protein. Gene silencing works by interfering with mRNA to inhibit the construction of the abnormal heme protein. So, although this is not a correction of the abnormal gene at the DNA level (a technique being developed for certain inherited diseases and discussed in prior columns), it can prevent the manifestations of porphyria by preventing the production of the abnormal protein.
Jeff Hersh, Ph.D., M.D., can be reached at DrHersh@juno.com