May 2005 PES Bulletin

A Brief Etiology of the Porphyrias

What is porphyria?
Where did it get it's name?
Who first diagnosed the disease? When?
Who were the leading first physicians/scientists?
What data supports the theory that many royals suffered with the disease?
Who are the other famous names who suffered this disease?
Where did porphyria get it's name?

Porphyria is a fascinating disease.
It is an Unknown Disease, but a very old disease going back to the beginning.
The Greeks have a word "porphyrus" which means the color purple.
The term "porphyria" and "porphyrin" are derived from this Greek word.
The urine of some patients, but not all, may present a reddish/purple coloring. Some researchers refer to it as port wine.
At one point in porphyria history researchers wanted to call the disease "pyrrolia"
The reason for this was due to the fact that the prominent metabolites are pyrroles. However the name never came to be used.
During the early years it was known as blood/liver disease.
Tests were not available for identifying the specific types, or mutations, and it was thought to be variants of all the same disease.
Now we have at least eight different distinct types and some others which are being researched at this time.

Where does one begin to tell the rich history of porphyria?
As long as there has been human life, there has been porphyria.
Porphyria began at the beginning of time and has continued to mutate throughout ensuing generations.
The name "porphyria" is only rather recent. For centuries it was known as blood/liver disease.
At one time the abdominal pain was actually thought to be from the liver.
In some cases it was because of victims dying from liver failure or liver cancer as an end results of the porphyria.
The first actual clinical description of the malaise has been attributed to a Dr. Schultz, who was a German graduate medical student in the year 1874. He gave it the name.
In some medical journals, they cite Hippocrates as the first to recognize porphyria. However the name is attributed to Schultz.
Probably the first clinical description of acute porphyria as a clinical syndrome was made by Dr. B.J. Stokvis in the year 1889. CEP porphyria was identified in the year 1923.
At first it was believed that there was error in the red blood pigment synthesis.
Today we know that porphyria is the over production of porphyrins in the liver. In other types the over production is found in the boine marrow.
Biochemical understanding of porphyria increased in the 1920's after the identification and classification of enzymes was made.
At this same time most of the major intermediates of the heme biosynthesis pathway were also identified.
In 1930 Hans Fischer, the Nobel laureate, described heme as the compound that makes blood red and grass green.
By 1937 Dr. Waldenstrom in Sweden published his findings.
For a time AIP was known as Swedish porphyria, or Waldenstrom's porphyria.
In the 1960's porphyria research began in earnest in Europe and in the US.
The big break came when scientists were able to recognize ALA and PBG in the 60's.
With modern technology came new molecular biology discoveries.
Then came DNA. And what was impossible a mere 12 years ago, is common place today in porphyria...family mutation identification and genetic mapping.

So this is a brief overview of the top names in our porph history.
However, blood/liver disease was recognized for years and was evident in the royal families for generations, as well as the VonGogh's family which ended with him.
Ironically the reason VonGogh drank the vermouth liquor was became he had the severe chronic abdominal pain...and the reason he got the ab pain was because he drank the alcohol.
A vicious cycle.
His vomiting caused such a great metabolic imbalance that it caused him such mental confusion that he literally ended his own life, and we lost a great artist.
Since 1989 the techniques of molecular buiology have been used to identify the mutations responsible for porphyria
HCP was isolated and identified. Since then Hardero porphyria has been isolated and identified as well as Chester porphyria.
Almost everyday now new mutations of AIP are being identified, along with new mutations, subtypes and dual traits among the other porphyrias.

Rosalind Meyers PhD, MNS
Genetics and Inherited Disease

GENETIC TESTING

A generic disorder is a disease, disability or physical deformity caused by some deviate gene formation. Any of the inherited types of porphyria are that, a deviate gene formation.
It may be the absence of a gene or part of the gene. Sometimes it is a mislocation of gene substance. And in some instances only one gene -- or part of one gene-- can cause the disorder. At other times it may have to be two or more genes which must be affected before a disorder becomes obvious.
In porphyria it all takes place in the heme pathway. In the heme synthesis.
Genes are composed of a long helix, as some have related it liken to two spiral staircases intertwined of deoxyribonucleic acid segments which we all know by the letters DNA.
It is the various combinations of these DNA units that impart function as well as heritary characteristics to the cells that make up body organs, tissues and even appearance.
It is believed that damage to DNA following excessive exposure to chemicals, drugs and ionizing radiation plays a critcal role in inherited genetic disorders such as porphyria.
DNA is also, in essencem the infecting material of bacteria and viruses, They insert their DNA into the body's cells and then reproduce themselves,causing disease.
AT present it is estimated that there are 15 million people in the United STates alone, suffering from some form of genetic disorder.
Because of this, it should be obvious, especially is there is knowledge -- or even the vaguest hint-- of a genetic-type illiness in the family tree.
It has been predicted that within a couple of years routine gene mapping will be commonplace, and that all laboratories will be eventually able to help determine an individual's susceptability to a great many inherited diseases.
The testing for a DNA marker for a specific disease is also entering the diagnostic field, and is available for porphyrics through Mt. Sinai Hospital in Manhattan, New York under the direction of Dr. Robert J. Desnick.
Dr. Astrin at Mt. Sinai has been overseeing the genetic testing of porphyria patients once confirmed diagnosis has been established through Dr. Karl Anderson at the University of Texas Medical School in Galveston.
At present only specific types of porphyria are being tested.
This is a form of gene probing that constitutes predictive testing for hereditary disease.

Genetic disorder screening has also been used as well to provide information to indirectly related parties such as insurance companies,health departments and motor vehicle bureas.
The availability of such data brings up the matter of confidentiality.
There is always the risk of such information reaching the wrong hands and causing almost as much disruption of one's life as the disease itself.
So, those who submit to such testing must be assured of the privacy of the results.
At the present time there ar well over 6,000 different inherited diseases or traits that are known [exhibited by the carriers of genetic diseases who do not usually show signs of the disease] .

The porphyrias reveal themselves as metabolic defects that interfere with normal body enzyme chemistry.
They can also be the consequence of the lack of one or more enzymes.
Genetic screening tests try to uncover individuals who have a greater-than-average-risk of passing on an inherited condition.

Gilda Wzarcipak PhD
Genetics

The Liver & Porphyria

The liver is a an important focus in the hepatic types of acute porphyria as well as some of the cutaneous forms.
Before focusing on the porphyria types and the liver, let us look chiefly at the liver itself. How much do we each know about our liver?
The liver is the largest internal organ in the human body.
The liver is the main organ that keeps you alive.
It is said of the liver that it performs over 100 separate bodily functions.
The sheer complexity of the liver makes it susceptible to almost as many different diseases.
Many of these diseases are rare, or like some types of porphyria, not rare, but hardly common either.
Of the common liver diseases some are "household names" that are all too common, including hepatitis, cirrhosis, liver disorders in children, alcohol-related disorders, and liver cancer.
In a report published in a medical journal in 1998, it states that over 25 million people are afflicted with liver and gallbladder disease each year.
Furthermore the report states that over 27,000 Americans die from cirrhosis annually.
With a mortality census like this, it makes cirrhosis of the liver the third leading cause of death for people between the ages of 25 and 59, and the seventh leading cause of death overall in the United States today.
Viruses, hereditary defects such as porphyria, and reactions to drugs and chemicals are among the known causes of liver breakdown.
Though few treatments are effective for life-threatening liver disease, avoiding alcohol and other substances known to cause damage can do a lot to safeguard this important organ.
Many drugs are unsafe for use in people with liver disease, so it is vital to read up on any pharmaceutical before taking it, even if your doctor has presecribed it for you.
This is especially true in porphyria.
If a drug is metabolized in the liver, you do not want to use it.
Porphyrins are manufactured in the liver.
With increased acute attacks or what some call chronic porphyria, the liver may be damaged more readily.
Avoiding drugs is imperative.
Seeking immediate Intervention Therapy is also imperative to reduce the risk of developing porphyrin crystallization in the liver.
So where is this organ that plays such a vital role in porphyria?
The liver is located behind the lower ribs, right below the diaphragm on the right side of the abdomen.
In an average-sized man, it is about the size of a football, weighing a little over three pounds.
The liver can be compared to an oil refinery, or a processing plant. The liver processes many chemicals necessary for the body's overall functioning.
For example, it converts carbohydrates, fats, and proteins into chemicals essential for life and growth.
The liver manufactures and exports to other organs some of the substances they need to function properly, such as the bile used by the intestines during digestion.
By now all of us know the word "metabolizes". This is done in the liver.
It modifies drugs taken to treat disease so that they can be used more easily by the body.
And the liver cleanses the blood of toxic substances either ingested or produced by the body iself.
But that's only part of the picture.

Below are some of the liver's many other important functions:
-Regulates the blood's ability to clot
-Governs the transport of fat stores
-Stores extra vitamins, minerals, and sugars to prevent shortages
-Produces quick energy as needed
-Controls the production and excretion of cholesterol
-Breaks down alcohol
Monitors and maintains the right level of numerous chemicals and drugs in the blood
-Maintains and controls hormone balance
-Helps the body resist infection by producing immune factors and cleansing bacteria from the blood
Stores iron

Viral hepatitis, a contagious infection of the liver, afflicts more than 70,000 Americans each year. It is usually caused by one of three different organisms.
Hepatitis A, formerly known as infectious hepatitis, can be contracted by consuming contaminated water or food, most notably shellfish.
Since the virus is eliminated in the stool, it also spreads through improper hand washing, especially by restaurant workers or anyone else who handles food.
Although hepatitis A is seldom serious, in one percent of the cases it can cause severe liver failure and death.
It does not cause chronic hepatitis and will not lead to cirrhosis or other long-term liver problems.
Hepatitis B, formerly known as serum hepatitis, is found in blood and other body fluids such as urine, tears, semen, breast milk, and vaginal secretions.
It is usually transmitted in blood, via transfusions, or through illicit injectable-drug use.
But it also can be contracted through a minor cut or abrasion, or during such everyday acts as toothbrushing, kissing, or having sex.
Infants can contract the disease from the mother at birth, or from the mother's breast milk.
Dental work, ear piercing, and tattooing are other ways people can get hepatitis B.
Type C hepatitis virus is the cause of a disease known as "non-A, non-B hepatitis," which is also contracted through contact with contaminated blood, or through household or sexual contact with an infected person. It affects approximately 170,000 Americans each year.
The problem with hepatitis B is that five to 10 percent of those who become infected with this disease become chronic carriers who can spread it to others for an indefinite period of time.
At present there are more than a million of these silent carriers in this country, and their number is growing by two to three percent annually.
Consequently, authorities recommend that all children and anyone with a high risk of exposure be vaccinated against this dangerous virus.
Chronic carriers usually do not develop chronic hepatitis. If it does develop, however, cirrhosis and primary cancer of the liver can be long-term consequences.
An estimated 4,000 people in the United States die from hepatitis B-related cirrhosis annually.
Carriers are many times more likely to get liver cancer than are non-carriers.
Treatment for acute hepatitis consists of rest and small, nourishing meals; fluids; and sometimes anti-nausea drugs such as trimethobenzamide (Tigan).
Chronic cases of hepatitis B and C are now being treated with interferon, a biotech medicine derived from the human immune system.

Randy Lipton PA
Hepatology & Gastroenterology

The Role of the Gallbladder

The gallbladder stores bile, a substance the liver produces to aid digestion.
The most common disorder of the gallbladder is the formation of gallstones.
These stones often get stuck in the bile ducts that lead from the gallbladder to the first part of the small intestine, causing the gallbladder to become inflamed.
Gallbladder surgery, in which the entire organ is removed, is one of the most common operations in this country.
Laparoscopic cholecystectomy, a new procedure that requires only a small incision, has cut down stress and recovery time dramatically.
Chenodiol, a recently available drug that dissolves gallstones, is an alternative to surgery.
However, due to limited success and troublesome side effects, it is not widely used.
Other Diseases of the Liver
In cirrhosis, liver cells are damaged and replaced by scar tissue which, as it accumulates, hardens the liver, diminishes blood flow, and causes even more cells to die.
The loss of liver function that accompanies this degenerative condition results in gastrointestinal disturbances, jaundice, enlargement of the liver and spleen, emaciation, and accumulation of fluid in the abdomen and other tissues.
Over half of the deaths related to cirrhosis are due to alcohol abuse, hepatitis, and other viruses.
Chemicals, poisons, too much iron or copper, and blockages of the bile duct also may cause the disease.
Treatment of cirrhosis usually consists of eliminating the underlying cause, if possible, to avoid further damage, and preventing or treating complications.
Care is mostly supportive, often including a specialized diet, diuretics (water pills), vitamins, and abstinence from alcohol. For some patients, a liver transplant is now a feasible option.
Liver abscesses are caused by bacteria, such as Escherichia coli (E. coli) or staphylococcus (staph), or by Entamoeba histolytica, the parasite that causes amebic dysentery.
In either case, the offending organisms destroy liver tissue, leaving a cavity that fills with other infectious organisms, white blood cells, and liquefied liver cells.
Common symptoms include shoulder and abdominal pain, fever, weight loss, chills, nausea, vomiting, anemia, and, if there is severe liver damage, jaundice.
If the offending organism can't be determined, liver abscesses are treated with long-term antibiotics such as aminoglycosides, cephalosporins, clindamycin, or chloramphenicol.
If E. coli is causing the infection, treatment includes ampicillin; for Entamoeba histolytica, chloroquine (Aralen), or metronidazole (Flagyl) are included.
Pediatric liver diseases afflict tens of thousands of children in this country annually, and kill hundreds each year.

More than 100 different liver diseases are found in infants and children. Most of these disorders are genetic.
Among the more common are:
Biliary atresia, an inadequate bile duct, often fatal but sometimes relieved by surgery; Chronic active hepatitis, in which scar tissue forms and destroys the liver; Wilson's disease, in which an abnormally large buildup of copper in the liver is treated with vitamin B6 and d-penicillamine, or, in some cases, corticosteroids such as prednisone; Reye's syndrome, an acute, often fatal disease secondary to flu or other infections in which fat accumulates in the liver and the patient lapses into coma.
Other serious diseases of the liver, fortunately seen less frequently than these discussed above, include fatty liver, hepatic coma, and liver cancer.

Randy Lipton PA
Hepatology & Gastroenterology

PORPHYRIA PAIN AND OPIOD ANALGESICS

Opioid analgesics are centrally acting agents.
These opiods provide fast pain relief by either binding or blocking opiate receptors in both the brain and the spinal cord.
An agonist effect is known as binding.
The blocking effect is known as an antagonist effect.
Opiods are also known as narcotics.
Opiods can play a role in the management of som chronic pain conditions and this includes many of the acute hepatic porphyric pain.
It is thought by many chronic pain specialists that non-addictive personalities of porphyria patients who use the opiods specifically for their analgesic effect have a very low possibility of addiction.
Those porphyria patients however who use such opiods because of the their euphoric effects have a far greater possibility of becoming addicted to such drugs.
Nonetheless, because of the social stigma and also in many places the legal issues that focus on the chronic use of opiods, there continues to be a barrier to both the patient's ability to comply and the physician's ability in prescribing.
For these reasons non-narcotic analgesics are often preferred as the first-line of therapy for porphyric patients for their often chronic pain.

Rodney Graham PhD, RPhm
Pharmacology & Toxicology