Chemical Injury and Disorders of Porphyrin Metabolism

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Chemical Injury and Disorders of Porphyrin Metabolism

http://www.mcsrr.org/resources/articles/S5.html

 

Some chemically-injured patients with Multiple Chemical Sensitivity (MCS)

show disturbances in their body's system for making heme, which is the primary

component of hemoglobin in red blood cells. Their lab tests reveal abnormal

activity in one or more of the eight enzymes involved in heme production. Since

most heme is made in the bone marrow, these " disorders of porphyrin metabolism "

are usually found there or in the liver. They can have a disruptive effect on

numerous processes that rely on heme and hemoglobin. Of clear concern to MCS

patients are the " cytochrome P450 " enzyme system, which uses heme to detoxify

chemicals in the liver and other vital organs, and the oxygen transport system,

which relies on hemoglobin to carry oxygen from the lungs to other body

organs.

 

Porphyria, Porphyrinuria and Porphyrinopathy

 

The term porphyria (pour-'fury-a) refers specifically to a group of diseases

in which cells in the liver and/or bone marrow (primarily) are unable to

properly carry out all the steps involved in making heme, due to an inherited

defect (or " inborn error " ) in one or more of the eight enzymes involved. The s

ymptoms that result may involve any part of the nervous system (central,

peripheral

and autonomic) or just the skin or both. Symptoms are triggered by exposure

to sunlight (in photosensitive cases) and/or by exposure to " porphyrogenic "

drugs or chemicals, infections and other stressors. When the heme-making pathway

is disrupted in this way, the excess porphyrins which are no longer

metabolized start to accumulate in certain body organs where they can have toxic

effects.

 

The most common type is Porphyria Cutanea Tarda, or PCT, which is one of four

non-acute porphyrias. Patients with PCT and the other non-acute porphyrias

have a variety of skin symptoms as a result of often severe " photosensitivity "

to sunlight. PCT also may be acquired in response to toxic drug or chemical

exposure and is made worse by such exposures. (In 1993, the Department of

Veterans Affairs accepted an Institute of Medicine recommendation to pay

compensation

to Vietnam Veterans with PCT, on the assumption that their PCT was most

likely caused or aggravated by exposure to the dioxin in Agent Orange.)

 

There also are four " acute " types of inherited porphyria which may display an

even wider variety of symptoms. They all feature neurological problems and

many also have psychological and/or skin symptoms. In three of these types, an

estimated 90% of those with the inherited enzyme deficiency have no symptoms

until their disease is triggered, often in mid-life, by some toxic drug,

chemical or metal exposure or by some internal stress such as liver disease,

hormonal

changes, or dieting. In acute types (and in PCT), once symptoms begin they

usually continue in response to many kinds of exposures and often include

chronic as well as acute aspects.

 

The term porphyrinuria (pour-'frin-ur-E-a) is used to categorize disorders of

porphyrin metabolism and excretion that are acquired from diseases, drugs or

chemicals with or without inherited enzyme abnormalities. These porphyrin

disorders usually are found in the liver and are called coprophyrinuria when

limited to coproporphyrins. Physical symptoms may be chronic, evident only

during

periods of acute attack, both chronic and acute, or they may be absent

altogether. Drugs and chemicals can cause porphyrinurias by triggering the

cytochrome

P450 system which in turn can overload the heme pathway. A secondary

porphyrinuria or coprophyrinuria is a porphyrin abnormality that occurs

secondarily to

some other disease which usually test positive for some but not all of the

diagnostic markers associated with true porphyrias.

 

The broader term " porphyrinopathy " is used here to refer to any disorder of

porphyrin metabolism, inherited or acquired. The porphyrinopathies being seen

in chemically-sensitive patients do not fit the patterns of any known type of

inherited porphyria. This suggests that they may be the result of an acquired

abnormality, due either to the direct effects of a chemically-induced

porphyrinopathy or the secondary effects of some other disease.

 

What kinds of symptoms are seen in Disorders of Porphyrin Metabolism?

 

The " acute " porphyrias always display neurological symptoms affecting the

central, peripheral and/or autonomic nervous systems. These may include any

combination of abdominal pain, nausea, vomiting, constipation, seizures,

headaches,

difficulty concentrating, personality changes, weakness and aching in muscles

and joints, unsteady gait, poor coordination, numbness/ tingling of arms and

legs, retaining fluids, rapid heart rate, increased blood pressure, increased

sweating, and intermittent fever.

 

Acute and chemically-acquired cases also show increased sensitivity to a long

list of exposures that may both bring on symptoms and make them worse. These

include certain medications (the focus of much porphyria research), toxic

chemicals (such as PCBs and dioxin), alcoholic beverages (including beer and

wine), other liver diseases (like Hepatitis C and cancer) as well as more subtle

factors like hormonal changes and a low carbohydrate diet. (Skipping meals and

dieting make symptoms worse, while chemicals that mimic the female hormone

estrogen are known to trigger acute porphyrias--both of which may contribute to

the higher incidence of acute porphyrias in females.) There is also one report

documenting acute skin sensitivity to copper in dental patients with

coproporphyria. (Copper is found in significant amounts in the silver and gold

used for

both dentistry and jewelry, and skin sensitivity can be tested easily by

wearing a copper bracelet; if sensitive, symptoms should appear in a few minutes

to

a few hours.)

 

When the skin is involved, as it is in all non-acute and some acute types,

symptoms from sensitivity to sunlight may include a wide variety of problems

such as rashes, blisters, changes in skin pigment, changes in facial hair, and

fragile skin that injures more easily. Porphyrinopathy patients also may

occasionally notice discolored urine, either dark brown or pink to red

( " port-wine "

colored) and not due to blood. It is from this sometimes dark purplish

color-- " porphyra " in Greek--that porphyria takes its name. (In the " Madness of

King

George, " a 1995 film about the acute porphyria that afflicted King George III,

the urine is portrayed as blue.) Any change in urine color is most likely to

occur during an illness reaction, and the dark color may be more obvious after

the urine has been left standing for a few hours exposed to light or heat.

(None of the underlined symptoms above would be expected in cases of MCS unless

due to a disorder of porphyrin metabolism.

 

Some persons with " acute " types of porphyria excrete porphyrin substances in

the urine and/or stool only in response to exposures that make them ill. Their

tests are more likely to show changes in the first 2 to 3 days after the

onset of a reaction. Thus, urine and stool testing is most sensitive and

accurate

during that time. Dr. Ziem recommends you not induce a reaction, but have the

lab form, and when a reaction occurs, go for the testing. The form explains

how to collect the specimens.

 

How are Disorders of Porphyrin Metabolism diagnosed?

 

Each type of porphyria is defined by specific symptoms and diagnostic signs

or " markers, " although these overlap considerably in some types. If a disorder

of porphyrin metabolism is suspected on the basis of symptoms, diagnostic

tests are usually ordered of urine and stool and sometimes also of blood and

plasma to look for characteristic abnormalities of enzyme(s), porphyrin(s)

and/or

porphyrin " precursors " (substances called ALA and PBG which are measured to

check the activity of the first two enzymes in the heme pathway). If acute

porphyria is suspected, this testing must be done when patients symptoms are

worse

than usual. Chemically-acquired porphyrinopathies are more variable and often

mimic one or more elements of the different inherited types, but they can be

tested and treated in the same way. Since ALA and PBG are always elevated in

urine during acute attacks, these porphyrin precursors are sometimes used alone

for screening potential cases. They may normal, however, in latent cases as

well as those in remission, in between attacks, and/or those with more chronic

symptoms. They also cannot distinguish between different types of

porphyrinopathy.

 

To be definitively diagnosed, an active case of inherited porphyria or

acquired porphyrinopathy should show evidence of all the following:

 

1. Abnormal enzyme activity in one or more of the eight porphyrin enzymes.

(Even if the patient has never had symptoms, this alone is enough to diagnosis a

latent case of porphyria.)

 

2. Abnormal levels of porphyrins and/or porphyrin precursors in the urine,

stool, blood and/or plasma (although they may be so only during acute attacks).

 

3. Acute and/or chronic symptoms typical of porphyrinopathies that are not

explainable by other diseases or other forms of chemical injury.

 

How can one be tested for Porphyrin Metabolism?

 

MCS Referral & Resources offers a detailed testing protocol developed by Dr.

Grace Ziem and Albert Donnay to assist doctors in evaluating disorders of

porphyrin metabolism in chemically-injured patients. It contains this fact sheet

as well as a laboratory request form, instructions for patients, diagnostic

information for physicians, interpretive tables, and a long list of drugs and

chemicals known to trigger symptoms of acute porphyrin disorders. We encourage

patients to discuss this protocol with their physician(s) to see if it is

appropriate for them. Any lab can collect the required blood, urine and stool

specimens, but the protocol requires that these be sent for analysis to the Mayo

Medical Laboratory, which is a world-renowned center for porphyria research.

 

Can the patient's family be affected?

 

The blood relatives of patients with an inherited porphyria may have the same

enzyme defect but no symptoms. About 90% of these " latent " or silent cases

never develop symptoms, but the other 10% are usually ill by mid-life. Since it

is not known which particular exposure(s) may eventually provoke their

disease, latent cases should be informed about the potential risk posed by

exposures

to " porphyrogenic " substances (like alcohol, and specific drugs and chemicals)

that may trigger their disease. This applies both at home and in the

workplace. MCS patients who test positive for abnormalities that are

characteristic of

one of the inherited porphyrias may want to encourage their immediate family

members to be tested as well, starting with their biological parents, if

possible. If both parents are normal, the porphyrin disorder is not inherited

and

other blood relatives (children, brothers and sisters) need not be tested.

 

How do Disorders of Porphyrin Metabolism relate to MCS?

 

Both conditions report increased sensitivity to certain chemicals, drugs and

alcohol. Many other symptoms are similar. Two separate medical practices in

Washington State have tested over 150 of their MCS patients with symptoms of

porphyrinopathy. According to analyses done by Mayo's Porphyria Lab, over 70% of

them had excess porphyrins and/or enzyme abnormalities in patterns that did

not match those of any inherited porphyrias. Disorders of porphyrin metabolism

may account for many of the symptoms seen in MCS cases (and possibly also cases

of CFS/CFIDS, fibromyalgia, Persian Gulf Syndrome and silicone breast implant

disease), but they do not explain all the symptoms and may not be present in

all cases, which suggests that other mechanisms of chemical injury must be

involved. Some MCS patients, for example, show evidence of direct neurotoxicity

in the brain, as well as impaired functioning of the limbic, respiratory and

immune systems, none of which are usually associated with porphyria or

porphyrinuria (although these have not been ruled out).

 

What if I have MCS symptoms but some or all of my tests are normal?

 

In some acute porphyrias and porphyrinurias, excess porphyrins and/or

porphyrin precursors may be evident only during an acute reaction. Testing

should be

repeated when you feel your symptoms are significantly increased and should

check for an excess of porphyrins in all possible locations: urine, stool,

plasma and whole blood. If repeated testing even when your MCS symptoms are

worse

than usual finds no abnormal levels of enzymes, porphyrins or their precursors,

then you do not have a disorder of porphyrin metabolism (at least not one

detectable by Mayo's current laboratory methods). These MCS cases may be called

" non-porphyric MCS " to distinguish them from those in which porphyrin disorders

are involved.

 

What can people with Disorders of Porphyrin Metabolism do to get better?

 

When secondary porphyrinurias are suspected, treatment should focus on the

primary disease causing the porphyrinuria. In the case of inherited porphyrias

and toxic acquired porphyrinurias, there is no known cure, but proper

precautions may greatly reduce symptoms and long-term damage to the body. As

with MCS,

the recommended " treatment " for acute porphyrinopathies focuses on the need

for patients to avoid all exposures that may provoke their symptoms. Patients

are advised strongly to:

 

1. Avoid exposures to " porphyrinogenic " chemicals, medications and other

substances known or suspected of making symptoms worse, including steroids and

anything that mimics estrogen. (Women with porphyria should inform their

gynecologist, since contraceptive pills may need to be avoided and pregnancy

closely

monitored.) Wear a Medic-Alert bracelet that says " Avoid Porphyrogenic

Substances: Chemically Sensitive. " (Call 1-800-432-5378 to order.) Avoid beer,

wine

and other beverages containing alcohol. Avoid activities that you find stressful

and seek prompt treatment for any other illness or infection, all of which

may provoke attacks. Before prescribing antibiotics, your doctor should confirm

bacterial infection with a " white count/differential " and/or culture to avoid

unnecessary medication. Avoid fasting, dieting, and a low carbohydrate intake

which can aggravate symptoms by causing the body to burn more fat, which is

where petrochemicals and many other toxins are stored. Symptoms may be reduced

by eating a regular diet of adequate carbohydrates and not skipping any meals.

Complex carbohydrates are best, such as potatoes and grains (bread, pasta,

cereal, etc. made from wheat, corn, oats, rye, and other grains). Because people

with chemical injury to the immune system are often more susceptible to

" yeast " (Candida) infections, they should not get their carbohydrates in the

form of

sucrose (refined sugar), although other kinds of sweets (such as the fructose

in fruit juice) are okay in modest amounts. If you suspect a food intolerance

or allergy, you should consult with a physician or nutritionist about ways of

identifying and avoiding problem foods.

 

If you are having an acute reaction, you can try to see whether sugars such

as fruit juice help your symptoms. Avoid iron supplements and vitamins

containing iron. Also avoid cookware made with uncoated iron or aluminum, since

these

metals can contaminate your food.

 

Consider having your serum iron tested if you frequently have diarrhea or

loose stools. Low normal is considered better for people with porphyrin

disorders. Another way to reduce iron levels in the body (if near or above

average) is

to slowly cut your meat intake. Be careful to get adequate protein from other

sources. Many people with a history of chemical injury have poorer absorption

of foods from their intestines. If you suspect this, discuss it with your

doctor. If you frequently have diarrhea or frequent loose stools, you probably

are

not absorbing food properly, and may need more protein (and nutrient

supplements without iron) to compensate for this. Avoid dehydration: drink at

least

two quarts of fluid over the course of the day. Do not count beverages that act

as diuretics, such as coffee, tea and sodas containing caffeine, since these

remove water from the body. If you drink these beverages at all, you should

drink extra water to avoid dehydration. Coffee aggravates symptoms in many MCS

patients, probably because caffeine is broken down by the same cytochrome P450

system in the liver which is affected by chemical injury. Remember that

decaffeinated coffee may still have as much as a third of the caffeine as

regular

coffee. In case of acute attack, try drinking beverages containing glucose or

fructose as well as lots of water (1-2 cups per hour minimum for several hours),

and eating a quick meal of carbohydrates. In cases of respiratory paralysis or

seizure, which can be life-threatening, doctors should consider immediate

injections of glucose or Panhematin (see below). For those whose symptoms are

worse in sunlight, avoid direct exposure to sunlight (even indoors through

glass)

and keep skin covered when exposed. Special sunscreens may help, but the best

protection is a broad-brimmed hat and clothing which covers most exposed skin

areas. MCS patients should avoid sunscreens that contain petrochemical

ingredients since these enter the body through the skin. It is very important

for

MCS patients to get outdoors daily for fresh air and exercise, since outdoor air

is usually less polluted. Try to avoid direct sun if you are photosensitive

(exercising at dawn or dusk, for example) and cover as much exposed skin as

possible. If you have to be out on hot days, try wearing silk--it's cooler than

cotton and protects skin well.

 

What medications may help people with Acute Porphyria or Porphyrinuria?

 

Attacks of acute porphyria may be treated with intravenous glucose

injections, special high glucose drinks (like HyCal, from Beecham), and heme

medications

such as Panhematin. These often help with acute symptoms but offer no lasting

cure. In cases of sustained or severe rapid heart beat or significant

hypertension, physicians should monitor the patient closely. Propanolol and

other

beta-blockers have been used to control these symptoms but since they sometimes

have severe side effects they only should be used under close medical

supervision (with monitoring of blood pressure and heart rate). Severe pain is

often

treated with narcotic analgesics, but also only under a doctor's supervision.

Some patients have reported benefits from drug-free approaches such as hypnosis

and acupuncture. Beta carotene (a vitamin found in carrots) is an antioxidant

believed to help reduce tissue damage from exposure to reactive chemicals. It

has been used to reduce skin symptoms in porphyria patients with some types of

photosensitivity, but neither it nor Vitamin E (another antioxidant) has been

found to help with other porphyria symptoms.

 

What drugs should be avoided by chemically-sensitive people with

Porphryinopathies?

 

Hundreds of drugs and chemicals that are known or suspected of triggering

symptoms in cases of acute and acquired porphyria have been identified, and

these

should be avoided unless medically essential. (A partial list is available

from MCS Referral & Resources.) Unfortunately, many thousands more have never

been tested. People with porphyria are likely to react badly to some

medications, have chemical injury in other body organ systems and beware could

react to

medications that are not believed to aggravate porphyria. Medications (and

chemicals) to avoid include those broken down by means of " oxidation " or

" hydroxylation, " steroids, those which mimic the female hormone estrogen, and

those

which induce the cytochrome P450 system in which heme plays such an important

role.

 

Although some lists of " safer " medications have been published by porphyria

researchers, new medications should be tried only one at a time and under close

medical supervision. They may not be safe in combination and reactions among

porphyria patients are known to vary significantly.

 

Chemically-sensitive patients with porphyrinopathies should wear a Medic

Alert bracelet, as noted above, and be sure to provide both Medic Alert and

their

local doctor with a list of the " porphyrogenic " medications to be avoided. If

your doctor prescribes any new medication, ask if it is broken down in the

body by oxidation or hydroxylation processes. If so, an alternative medication

should be considered.

 

Will medical insurance pay for testing and treatment of Porphryrin Disorders?

 

 

It should. Disorders of porphyrin metabolism, although rare, are widely

accepted by the medical community, and " porphyrinurias " have been listed by the

International Classification of Diseases since 1920 (currently ICD 277.1). The

diagnostic need for detailed biochemical testing is well established in the

medical literature (urine and/or stool testing alone are insufficient). There

also

is broad agreement that the primary focus of treatment in acute cases must be

on the avoidance of exposures that may trigger an attack, just as recommended

for MCS. Since so many types of porphyria have such potentially serious

consequences, there is no excuse for denying complete and prompt evaluation in

any

suspected case.

 

Please let your physician and MCS Referral & Resources know if your insurance

company refuses to pay for porphyria diagnosis and/or treatment. You may want

to appeal, and we may be able to help.

 

References and Recommended Reading:

A packet of medical papers on porphyria and a brief bibliography are

available from the National Digestive Diseases Information Clearinghouse,

301-654-3810.

 

You also may wish to contact the American Porphyria Foundation

(713-266-9617), which publishes a newsletter and brochures about different

aspects of the

inherited porphyrias and their treatment (via diet and hematin, for example).

Except for Porphyria Cutanea Tarda, however, they offer no information on

chemically-acquired disorders of porphyrin metabolism or " porphyrinuria. "

 

Berkow R (ed.) 1992. The Merck Manual of Diagnosis and Therapy, 16th edition,

Rahway, NJ: Merck Research Laboratories, pp. 1026-1038.

 

Bloomer JR and HL Bonkovsky. 1989. " The Porphyrias, " Disease-a-Month, vol.35,

no.1, pp.1-54.

 

Kappas A, S Sassa, RA Galbraith, and Y Norman. 1989. " The Porphyrias " in The

Metabolic Basis of Inherited Disease, Scriver CR, AL Beaudet, WS Sly, and D

Valle (editors), 6th edition, New York: McGraw-Hill Information Services

Company, pp.1305-1365.

 

Moore MR, KEL McColl, C Rimington, and A Goldberg. 1987. Disorders of

Porphyrin Metabolism, New York: Plenum Medical Book Company.

 

Scriver CR, AL Beaudet, WS Sly, and D Valle (editors). 1995. The Metabolic

Basis of Inherited Disease, 7th edition. New York: McGraw-Hill Information

Services Company, 2103-2159.

 

Silbergeld EK and BA Fowler (editors). 1987. Mechanisms of Chemical Induced

Porphyrinopathies, Annals of the New York Academy of Sciences, volume 514