Porphyria Educational
Services
Monthly Newsletter
Vol. 3 No. 2 February 2001
FOCUS: Enzymes and The Heme Pathway
When one begins to look at the inherited metabolic disease
porphyia, one will be confronted with the basics of the heme
biosynthetic pathway which is a curcial focal point of the
porphyrias.
The enzymes that drive the heme biosynthetic pathway are: (1)
d-aminolevulinate (ALA) synthetase, (2) ALA dehydratase, (3)
uroporphyrinogen I synthetase (PBG deaminase) and
uroporphyrinogen III cosynthetase, two enzymes that work in
concert, (4) uroporphyrinogen decarboxylase, (5)
coproporphyrinogen oxidase, (6) protoporphyrinogen oxidase, and
(7) ferrochelatase (heme synthetase).
Spilled porphyrins derived from porphyrinogens with 8, 7, 6, 5,
and 4-carboxyl groups are largely excreted in the urine while the
less polar 2-carboxyporphyrin as known as protoporphyrin, is
excreted exclusively in the feces.
The physiologically relevant pathway leading to heme is that
leading via uroporphyrinogen III, in which the propionyl and
acetyl groups are "reversed" compared to those of the
type I pathway, which "dead ends" with coprophyrinogen
I.
The physiological significance of the type I pathway remains
unclear; however, coproporphyrin I is elevated in hepatobiliary
diseases and arsenic toxicity.
Each specific type of porphyrias is determined by the elevations
of certain enzymes in the
heme biosynthetic pathway.
Lori Mattson, PhD
BioMedical Clinical Research
FOCUS: Liver Damage and Drugs in Porphyria
Most porphyria in itself is hard on the liver. When you add the
use of many pharmaceuticals you run the risk of increasing your
risks for liver damage.
Various pharmaceuticals are an important cause of liver
damage.The mechanisms are variable, complex, and, in most
instances, not well understood.
It is known that some pharmaceuticals cause direct toxicity:
Injury is generally predictable, dose-related, and characteristic
for the drug. This is especially true in porphyria patients and
the use of cytochrome P-450 pharmaceuticals.
Other pharmaceuticals produce damage only rarely in susceptible
persons; the injury is generally unpredictable. In these cases
such damage is generally not dose-related.
Although susceptibility is often regarded as hypersensitivity,
evidence of a true allergic reaction is usually lacking;
idiosyncrasy is the preferred term for this response according to
many in pharmacology as well as hepatology and
gastroenterology.The distinction between direct toxicity and
idiosyncrasy is not well understood, and is less so now than was
previously thought/ This is especially true when pharmaceuticals
have been administered e in susceptible patients.
It is well to note here that some pharaceuticals previously
considered allergens appear to damage cell membranes directly via
toxic intermediate metabolites.
There is no classification of liver damage caused by
pharmaceuticals is completely satisfactory. Most acute cases can
be divided into hepatocellular, cholestatic and miscellaneous
reactions.
Furthermore some pharmaceuticals rugs can produce chronic damage,
including tumors. Mild jaundice can occur from chemically-induced
hemolysis with unconjugated hyperbilirubinemia, but no true
hepatic damage occurs and liver function tests are normal.
Use of tetracycline especially in high dosage is known to produce
fatty infiltration with a clinical picture resembling hepatitis.
Acute overuse of the non-narcotic analgesic acetaminophen has
become an important cause of fulminant liver failure. The high
use of the drug depletes the liver of glutathione, which normally
detoxifies the drug by binding potentially hazardous intermediate
metabolites. Such liver damage is often not apparent until 2 to 5
days after ingestion of acetaminophen.
Evidence also incriminates acetaminophen in chronic liver damage.
Some pharmaceuticals can produce acute hepatocellular necrosis
that is clinically, biochemically, and histologically
indistinguishable from viral hepatitis. Offending agents are
numerous and include isoniazid, methyldopa, monoamine oxidase
inhibitors, indomethacin, propylthiouracil, phenytoin,
diclofenac, and the anesthetic halothane. Porphyria patients
should learn at the time of diagnosis that most pharmaceuticals
are unsafe for them and such use will run the risk of
exacerbation of their porphyria as well as asking for liver
damage.
Some pharmaceuticals such as aminosalicylic acid, sulfonamides,
several other antibiotics, quinidine, allopurinol, valproic acid,
aspirin can cause mixed forms of hepatic dysfunction. One such
dysfunction is that of a granulomatous reaction, or variants of
liver injury difficult to classify.
Many antineoplastic drugs also cause liver damage; the mechanisms
vary.
The pharmaceuticals Isoniazid, methyldopa, and nitrofurantoin can
produce ongoing liver damage and are indistinguishable from
chronic hepatitis. The illness may begin as an acute hepatitis or
more insidiously. Progression to cirrhosis may occur.
The cardiac drug amiodarone occasionally produces chronic liver
injury that histologically mimics alcoholic liver disease.
The pharmaceutical chlorpromazine has produced chronic
cholestasis with biliary fibrosis.
A sclerosing cholangitis-like syndrome can develop from hepatic
intra-arterial infusion of
chemotherapy, especially with floxuridine.
Arthritis patients receiving long-term methotrexate can develop
insidiously progressive hepatic scarring. Liver function tests
are typically unremarkable, and liver biopsy is needed for
diagnosis.
Chronic liver disease and hepatocellular carcinoma are believed
to result from ingesting
foods containing fungal products known as aflatoxins.
Roger Simpson PhD
Heptology & Gatroentrology Research
FOCUS: Hyponatremia and Porphyria
Hyponatremia deals with one part of the electrolyte imbalance
which often occurs as a part of acute attacks of porphyria.
Hyponatremia occurs when the body has less than the normal amount
of sodium in the blood. Realization of this less than normal
range of sodium is determined through a collection of blood from
a patient. Most often it is a part of the routine electrolyte
panel which is administered as a patient is admitted to the
hospital where they will begin intervention therapy for the
porphyria.
If hyponatremia is left undiagnosed and untreated theporphyria
patient will most likely develp water intoxification. In addition
the patient will usually present with confuion and lethargy
leading to muscle spasms, convulsions and coma.
Laboratory tests to check the ranges of all electrolytes is most
essential to be administered to all porphyria patients during
acute attacks. Hyponatremia is most notable for its frequency and
intensity during acute attacks in over 50% of porphyria patients.
Increase in urinary porphobilinogen, is also often observed.
In addition septic complications, such as pneumonia, septicemia,
and urinary tract infection, present in over 50% of acute attacks
requiring hospitalization..
Administration of needed electrolytes in conjunction with the
necessary administration of carbohydrates will most often correct
the sodium levels. It is most important to followup with further
electrolyte testing as the porphyria patient begins into
remisison.
Karen Simmons, RN, NP
Intensive Care
FOCUS: Diagnosis of Abdominal Pain in Acute Porphyria
The majority of porphyria patients with a confirmed diagnosis can
recall the unexplained abdominal pain that made it's presence
known time and again, and often being made to feel
"suspect" or told that they were "imagining
it" or that the pain was "all in their head".
Abdominal pain accounts for 42% of emergency department visits in
a study that was made and a report that recently released.
Physicians know well that hardly a day goes by that they have at
least one patient presenting with a case of abdominal pain on
their shift.
There are many possible causes for abdominal pain. For the
physician, whether the family physician and primary care
provider, or for the emergency room doctor, he challenge lies in
distinguishing between the seriously ill patients who require
immediate attention and those who can safely be sent home. And
what of this pain? What is it's cause? And how often does this
pain present?
Skillful history taking and physical examination are often
sufficient for the task, although imaging studies may be needed
such as xray, CT scans, MRI or doppler.Distinguishing between the
different causes of abdominal pain will be the major task
presented for the
physician.
Furthermore, interpreting important laboratory data, and ordering
the right study to
affirm a diagnosis, is equally challenging and foremost.
When a patient presents several times fwith the same symptoms,
often, all the information the physician will need to make the
correct diagnosis will be contained in the history and physical
exam. And one more step is to get a thorough medical history log
of the patient's
family which includes the patients and sibblings. Here within
lies the answer of possible
genetic disease.
Differential diagnosis as it is termed, is of foremost importance
with a patient which presents time and again with the same
abdominal pain. The physician must rule out all of the following
and can do so easily by asking the right medical history
questions.
Diagnostic possibilities in acute abdominal pain include -- but
are not limited to -- (1) acute cholecystitis, (2) appendicitis,
(3) biliary or renal colic, (4) ectopic pregnancy, (5) intestinal
obstruction, (6) pancreatitis, (7) pelvic inflammatory disease
(PID), (8) perforated peptic ulcer, and (9) ruptured abdominal
aortic aneurysm (AAA).
Things to be kept in mind by the physician examining a hepatic
porphyria patient are the cardiac risk factors especially if the
patient complains of nausea and vomiting along with the abdominal
pain. It is not the usual scenario for cardiac problems and more
often is gastroenteritis. But abdominal pain can be life
threatening and especially when it involves cardiac problems.
In examining a patient with unexplained abdominal pain, it is
foremost to consider the worst possibilities first as those
require immediate intervention. Acute appendicitis
is always one of the first things to be considered on a check
list. With a majority of porphyria patients, their appendix was
removed unnnecessarily because it was thought to be the cause of
thje abdominal pain at some earlier time. Intestinal blockage has
also often been an incorrect diagnosis for porphyic abdominal
pain.
However, it is most important to begin hydration of a patient who
is suspect for porphyria. Long hours of waiting in an examination
room only adds to the problem of the acute attack. Early
administration of glucose infusion will in fact reduce the pain
index within a few hours as it is the action of the carbohydrate
infusion that corrects the over production of porphyrins in the
liver. And while porphyric pain is not well understood, but
nevertheless is a known factor, the administration of glucose
will stop the overproduction of porphyrins and at the same time
reduce the abdominal pain which signals the onset of acute
porphyric attacks.
Porphyria is not an everyday scenario in the clinical setting
unless a physician is a porphyria specialist. It is hoped that
all primary care providers will keep an open mind in dealing with
unexplained abdominal pain. The signs are not alway clear cut,
and porphyria does require a high degree of suspicion. But always
remember that in porphyria patients that the pain while hard to
determine, is real, and not just a imaginary condition.
Differentiating PID from appendicitis is among the most difficult
problems in an urgent care unit. medicine. More times than not,
porphyria patients have had to undergo a laparoscopy in order to
rule out various medical conditions.
For women of childbearing age even with a given confirmed
diagnosis, a beta [bHCG] screening test for pregnancy should be
administered. Ultrasonography can often help rule out
appendicitis, ovarian cysts, and ectopic pregnancy.
Once again, obtaining a detailed history as you perform the
abdominal examination is most critical. Porphyria patients should
be asked to characterize the pain and describe its location,
onset, and duration. Pain descriptions are subjective, and no
report is diagnostic. Many porphyria p[atients carry with them a
pain rating index which will help with understanding the exact
nature of the pain. The porphyria pain scale is used because
often the porphyria patient as time before treatment lags,
experiences increased weakness, may experience seizures, and
mental confusion, and nausea and vomiting increases.
Dr. Robert Johnson, MD
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Monthly
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the disease porphyria
and it's associated symptoms, triggers, and treatment.
Columnist and contributors and the information that they provide
are not intended
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diagnosis and treatment
of the porphyrias are based upon the entire encounter between a
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