September 2005 PES Bulletin

PORPHYRICS & CHRONIC PAIN

Porphyric pain may be acute or chronic.
Acute pain is a one-dimensional pain.
This means that it is a symptom of an underlying pathology.
The primary goal of pain management therapy would be the treatment of the underlying disease which reduces or eliminates the pain. [We hope!!!]
Analgesics are used as adjunctive medications to provide short term comfort and prevent behaviors that interfere with the recovery process from an acute attack of porphyria.
On the other-hand chronic pain is a multi-dimensional type of pain.

It is very complex.
Because of the complexity the interplay between between the psychological, physical and social factors can actually worsen the symptoms.
There are three types of chronic pain.
The first is pain resulting from a chronic condition.

Sound familiar? So it is with most porphyria pain.
Chronic pain in and by itself may be considered a disease.
In this case reducing or eliminating the pain without increasing the risks is the primary desired result of treatment therapy.
In a 1998 study it was estimated that more than 75 million people in the United States alone have some kind of persistent recurrent pain.
Among these are those who suffer lower back pain and chronic tension headaches.
Chronic pain as most porphyrics so well know, affects all aspects of their lives.
Pain is described as being "an unpleasant sensory and emotional experience arising from actual or potential tissue damage .
The dual physical and emotional aspectsof the definition are important to remember because they are so very conencted.
The physiological and physical effects of pain include increased pulse, blood pressure, and respiration.
It also means decreased activity and mobility.
In addition chronic pain also causes fatigue, sleep disruption or restlessness, anxiety, agitation, anger, and all too often, depressiobn.
Some aspects become too prevalent in a porphyric's life that they literally become unable to function.
The social consequences of pain include disruption of family life and also decreased productivity.

Regina Watson MNS, NP-C
Pain Management

Neuropathy in Acute Porphyrias

Neuropathy is a general term for disorders of the peripheral nervous system.
Neuropathies may affect just one nerve (mononeuropathy) or several nerves (polyneuropathy).
In the acute porphyrias neuropathies are often referred to as PN.
Depending on the nerves involved, symptoms can range from a mild tingling or numbness in the fingers or toes to searing hand or foot pain.
A porphyria patient may lose some of the feeling in the feet or the hands.
Some porphyria patients might also experience weakness or even paralysis of certain muscles, including problems with the bowels or bladder.
Neuropathy stems from damage to nerves.
If nerves related to digestion are damaged, your stomach may empty too slowly.
When the stomach empties too slowly there may be constant nausea, vomiting and bloating.
Porphyria patients with digestive neuropathy may have frequent constipation or diarrhea.
In some pporphyria patients there may problems with bladder control. Bladder dysfunction is often noted during episodes of acute porphyria.
Neuropathy symptoms result from damage to the nerves that provide communication between the brain and other parts of the body.
Parts of the body can include the muscles, skin, internal organs and blood vessels.
Peripheral neuropathy often affects people with diabetes and autoimmune diseases such as rheumatoid arthritis and lupusas well as those with the acute porphyrias.
Certain vitamin deficiencies, as well as some neurotoxic medications can also damage peripheral nerves.
Neuropathy among PCT patients is often due to the use of alcohol.
Partial or complete loss of movement or sensation has been documented in some acute porphyria patients both during an acute episode and sometimes contonuing into periods of remission.
Difficulty breathing or swallowing can occur in more severe bouts of neuropathy in porphyria patients.
These conditions are known as bulbar paralysis or respiratory paralysis and both can be life threatening to an acute porphyria pagtient.
Bone and muscle pain often are found in porphyric neuropathy.
Problems with one's balance can occur especially in those with loss of sensation in the feet and ankles.
Neuropathy can leave a porphyria patients with periods of restlessness and insomnia.
Depression sometimes occurs in conjunction with neuropathy.
Treating the underlying condition of PN can relieve some cases of peripheral neuropathy.
Avoiding acute episodes of porphyria helps avoid progression of neuropathy in the acute porphyrias.
For some porphyria patients with severe neuropathy the treatment may focus on managing pain.
It is good to note here that the peripheral nerves have a remarkable ability to regenerate themselves.
Often nerve damage does not remain permanent in the acute porphyrias.
More permanent neuropathy is found in PCT patients where the PCT has been triggered by the use of alcohol.

Sophia Ellsmore NP
Neurology

Heme, Cytochrome P-450 and Porphyria

Heme Biosynthesis is the backbone of the porphyrias.
Heme is synthesized in largest amounts by the bone marrow.
In the bone marrow the heme is incorporated into hemoglobin.
The hemoglobin which is an oxygen transport protein takes it from there.
The heme is then off to the liver. At the liver the heme is metabolized by the liver, where most of the heme is incorporated into cytochromes.
The cytochromes are electron transport proteins.
The most abundant cytochromes in liver are the cytochrome P-450 enzymes that metabolize drugs and many other foreign and endogenous chemicals.
It is for this reason that all porphyrics must be very careful in avoiding all drugs that metabolize in the liver.
Such drugs are often referred to as P-450 drugs or toxins.
Heme biosynthesis is controlled differently in liver and bone marrow.
Hepatic heme biosynthesis is rate-limited and primarily regulated by the first enzyme, ALA synthase.
This enzyme's activity in liver cells is normally very low but increases dramatically by induction of enzyme synthesis when the liver produces more heme.
Certain drugs and hormones induce hepatocytes to make more ALA synthase, heme, and cytochrome P-450.
In the bone marrow, heme is made in erythroblasts and reticulocytes that still contain mitochondria, whereas circulating erythrocytes lack mitochondria and cannot form heme.
Bone marrow cells express erythroid-specific forms of some pathway enzymes.
Porphyrias and related disorders are associated with deficiencies of the other seven enzymes.
Although each type of hereditary porphyria is associated with deficiency of a particular enzyme, unless people with that enzyme deficiency come from the same family, they are likely to have different mutations in the gene for that enzyme.
Because of this factors these diseases are heterogeneous at the molecular level.
Some porphyrias, especially those that increase the early precursors ALA and PBG, damage nerves, leading to a variety of symptoms such as abdominal pain and muscle weakness, which can even progress to paralysis.
Mechanisms for the neurologic disturbances have been speculated, such as effects of excessive heme pathway intermediates, or deficient heme synthesis, in the nervous system. ALA and other products of the heme biosynthetic pathway have not been proven to be neurotoxic, and heme deficiency in nervous tissue in these disorders is also unproven.
Therefore, the exact cause remains unclear.

Sylvia Gutierrez PhD
Biochemistry & Genetics Research

Environmental Factors and the Porphyrias

Environmental factors are a trigger for some types of porphyria.
No doubt about it anymore.
More and More is being learned and studies are now showing that a large number of porphyric patients have an exacerbation of symptoms due to environmental causes.
In an abstract published in "Nature and Genetics" [1996 12:195-199] by Dr. Grandchamp of Paris, France and a world reknown porphyria expert, he states: "It is now known that attacks of acute intermittent porphyria are often precipatated by environmenta; factors.
For this reason, early detection of gene carriers is important in the prevention of acute attacks, because affected patients, even though asymptomatic, can be instructed to avoid precipating factors."

So it is necessary to detect who the gene carriers are in our families and begin preventative majors as to avoid carriers going from asymptomatic to acute active porphyrics.
It can be done, and we must move in this direction.
We also need to move to more and more preventative treatment rather than waiting for acute attacks to cause us unneccesary and costly hospitalization.
In a paper titled "Redefinition of Abnormal Susceptibility to Environmental Chemicals: given by the respected and knowledgeable Dr. William E. Morton MD, a porphyria diagnostian, before an International gatherings some years back in Atlanta, Georgia, Dr. Morton recognizes that many doctors are missing the correct diagnosis.
Dr. Morton states: "For some time we have known of persons who manifest extreme intolerance for small exposures to environmental chemicals."
He goes on to say that "During the last several years, Mayo Laboratory's introduction of several new blood-cell porphyrin enzyme tests has permitted recognition of a broader spectrum of porphyria cases than previously. Many of these milder and more chronic porphyria cases have characteristics of MCSS, which appear after the porphyrin enzyme deficiency has converted from latency to metabolic activity by porphyrogenic substance exposure."
In talking about the symptomology of porphyria Dr. Morton stated "Porphyria symptoms can be quite variable, ranging from severe acute attacks to continuing low-grade smoldering symptoms to asymptomatic latency.
The porphyrias used to be considered very rare conditions [under 200,000 known cases], discoverable only during an acute attack when porphyrin excretion was markedly excessive.
Happily today as Dr. Morton points out, " The newly available and much more sensitive blood-cell enzyme tests have naturally resulted in greatly increased population frequency estimates (4%- 9%, up from 0.01-0.1%) in agreement with estimates made more than a century ago."
So what are the environmental factors that cause this increase of acute porphyrics?
Environmental porphyrogenic substances include paints and paint fumes, expoxies, metal dusts and fumes,alcohols [especially ethanol], freons, arsenic, biphenyls [PCBs], DDT, chlordane, glycols, glycol ethers and derivatives, vinyl chloride fumes and dust, , polychlorinated, formaldehyde, other aldehydes, freons, dioxins, hexachlorobenzene chlorophenoxy acetic acids, heavy vehuicle exhaust fumes, perfumes and other fragrances, tetracloro dibenzodioxins [TCBCs] chlorine, chlorinated cleaning agents,and many others that continue to be identified by medical researchers around the world.
In respect for the environmental factors porphyrics and those who are highly suspect for porphyria because of familial histories of porphyria should seek testing and then take all precautions known for avoiding exposure to these environmental factors.
This can come through identification of index and related latent cases allowing for the control of symptoms by preventive avoidance of porphyrogenic materials.

MaryBeth Reasoner MNS
Inherited Metabolic Diseases