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
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
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
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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