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* This unit will focus on what a general physician needs to know about the porphyrias. DO NOT go back and memorize the porphyrin section of Stryer!

* Dividing porphyrias into "hepatic" ("caused by accumulation of precursors of the P450 cytochrome") and "erythropoietic" ("caused by accumulation of precursors of hemoglobin") is becoming unfashionable. Despite the problems making porphyrins, the metabolic machinery goes into overdrive so patients are seldom anemic. All about the LAB DIAGNOSIS of porphyrias: NEJM 324: 143, 1991; update J. Clin. Path. 54: 500, 2001. Diaper diagnosis of erythropoietic porphyria (all you need is a diaper and a hippie's ultraviolet light): NEJM 330: 119, 1994. Porphyria in children: Mayo Clin. Proc. 77: 825, 2002 (kids); Am. J. Clin. Path. 119(S): S-86, 2003.

MECHANISMS AND SYMPTOMATOLOGY IN THE PORPHYRIAS

{09199} porphyria

Most current thinking focuses on accumulations of toxic metabolites.

DELTA-AMINO LEVULINIC ACID and PORPHOBILINOGEN are neurotoxins that produce cerebral dysfunction and damage (confusion, "psychiatric disease"), autonomic neuropathy (constipation, urinary retention, tachycardia, hypertension) and severe (sometimes chronic) abdominal pain.

These porphyrias imitate other many diseases, from acute appendicitis to acute schizophrenia. Between attacks, patients have mild symptoms, including "psychoneuroses". Obviously, making the correct diagnosis is important. (Up to 1 in 300 psychiatric patients has AIP.)

Delta-amino levulinic acid may be a false transmitter for gamma-amino butyric acid. It also blocks one of ATP-ases (perhaps a sodium pump) in nervous tissue.

Urine rich in porphobilinogen turns reddish-purple (uroporphyrin) on long exposure to bright light (toilet, ward station, lab). "Porphyria" means "purple".

UROPORPHYRINOGEN and PROTOPORPHYRIN when exposed to light generate free radicals.

* Uroporphyrin is mostly in the cytoplasm, while protoporphyrin is mostly in mitochondria. Both are damaged by light exposure.

The worst wavelength is 400 microns (* "the Soret band", responsible for the orange-red fluorescence), which is not screened out by window glass or standard sun-screens. These patients need to use opaque stuff on their skin. Beta-carotene, which absorbs the problem photons, is another mainstay of their therapy.

Patients with these porphyrias suffer blistering (subepidermal separation) and scarring of the skin. Look especially on the backs of the hands.

* A pathologist suspects porphyria even in unblistered skin by finding PAS-positive cell debris around dermal capillaries. Grossly, healing lesions are often mistaken for scleroderma.

On nerve biopsy, findings are nonspecific; the axons are selectively damaged rather than the myelin.

For some reason uroporphyrinogen also causes increased lanugo hairs ("hypertrichosis"). Look especially over the cheeks and temples.

Other current ideas about how porphyrias cause symptoms focus on the actual LACK OF HEME MOIETIES IN TISSUE. This is difficult to study but makes sense.

ACUTE INTERMITTENT PORPHYRIA (AIP -- see Neurology 48: 1678, 1997)

This autosomal dominant disorder is due to a partial deficiency of uroporphyrinogen I synthetase (porphobilinogen deaminase).

You can measure the level of the enzyme in RBC's to detect even latent AIP. This is now the preferred means of making the diagnosis; of course, you need a specialty lab.

* By now, a host of different alleles are known, and which type Is present correlates with severity (Medicine 84: 35, 2005).

* The homozygous form is of course a disaster: Neurology 61: 1764, 2004.

During acute episodes, the patient typically has severe colicky ABDOMINAL PAIN and/or "PSYCHIATRIC DISTURBANCES". Most are tachycardiac (helpful in following the illness), and hypertension and leukocytosis are common.

MRI scans show vascular mayhem in the brain in acute intermittent porphyria (Neurology 41: 1300, 1991).

* Poe's Roderick Usher ("Fall of the House of...") was perhaps based on someone with acute intermittent porphyria (JAMA 261: 863, 1989). UMKC's Loretta Loftus et. al. suggests porphyria as the cause of Vincent VanGogh's craziness (Br. Med. J. 303: 1589, 1991).

Especially suspect AIP whenever a patient has suggestive signs after taking BARBITURATES (which increase ALA synthesis).

Oral contraceptives, sulfa drugs, ketoacidosis, cocaine (Lancet 2: 1150, 1987), fasting, and acute infections also precipitate attacks. (These patients need a Medi-alert bracelet.)

The BASIC LAB TEST FOR AIP is URINARY PORPHOBILINOGEN. (Indications for this test includes elements of the clinical picture outlined above. Be suspicious! One patient in 1000 has at least the genetic potential to express AIP.)

Urine porphobilinogen will be increased during acute episodes (at least) of AIP (* also variegate porphyria and coproporphyria.)

* Theoretically, the urine "dipstick" test for urobilinogen should record porphobilinogen, too. This just doesn't work in practice, because porphobilinogen is very unstable and there's not enough to turn color anyway.

You must collect the urine for porphobilinogen assay in a LIGHT-PROOF BOTTLE (wrap it in aluminum foil.) It helps if the urine is ALKALINIZED. (Add an "amp of bicarb"; or alkalinize the patient.) Most important, the urine must be REFRIGERATED.

Even if you see purple urine, get confirmation on a super-fresh or very-well-refrigerated specimen.

* The traditional screening tests for porphobilinogen are extraction-based traditional-bench-chemistry tests called the "Watson-Schwartz" and "Hoesch" tests, and you may hear these names. These are NOT sufficiently sensitive for routine screening (Am. J. Clin. Path. 92: 644, 1989).

Today's lab will use high pressure liquid chromatography to screen for delta-amino levulinic acid and porphobilinogen.

* If you need further tests to establish the diagnosis of acute intermittent porphyria, get consultation.

You may order urinary uroporphyrin (will be high), urinary delta-amino levulinic acid, and/or red cell porphobilinogen deaminase (detects the latent illness).

You may also discover the patient has inappropriate hADH production and increased thyroid binding globulin, though this is not part of the work-up.

* You will learn how to treat acute intermittent porphyria on rotations. Specific remedies have included heme derivatives plus glucose. Both inhibit the synthesis of amino-levulinic acid. Today's "Panhematin" is hemin, an iron-containing porphyrin and generally recognized as effective (Am. J. Med. 119: 801.e19, 2006 -- bewails the ongoing problem of missed diagnoses). Liver transplant for cure: Lancet 363: 705, 2004.

VARIEGATE PORPHYRIA

This disease, similar in symptoms to AIP but with photosensitization as well, probably afflicted the European royal families -- King James (Bible Version), George III (American revolution, update Lancet 366: 332, 2005 supports the claim and also finds arsenic from quack treatments in his hair, which could have exacerbated things), Mary Queen of Scots, and others all had symptoms, and some of their living descendants are affected (Br. Med. J. 1: 7, 1968).

To make this diagnosis, measure protoporphyrinogen oxidase after puberty (S. Afr. Med. J. 70: 819, 1986 -- this disease is very common in South African whites because of a founder effect). Gung-ho clinicians now aspirate duodenal bile or cannulate the common bile duct to measure bile porphyrins (* protoporphyrin is soluble in bile but not in urine), establishing the diagnosis between attacks (NEJM 324: 1432, 1991, works great). Homozygotes are severely affected (Clin. Genet. 32: 300, 1987).

COPROPORPHYRIA

Deficiency of coproporphyrinogen oxidase. This fortunately rare disease is similar to AIP, and can be a noxious pain syndrome.

* The present-day pop diagnosis of "multiple chemical sensitivities" has been proposed to be a forme fruste of coproporphyria.

The idea is that since certain chemicals in large quantities can give anybody porphyria with vague mental and physical complaints, then certain people must have similar complaints because they are super-sensitive to many other chemicals.

This obviously doesn't make sense, and the latest review describes a fundamentally flawed assay by the lab making the connection: Arch. Int. Med. 157: 281, 1997.

More about "MCS", later, along with why almost no one in scientific medicine believes in it any more, and how its proponents operate.

PORPHYRIA CUTANEA TARDA (familiar as "PCT")

This commonest of the porphyrias is due to a partial deficiency of uroporphyrinogen decarboxylase. (Molecular biology: Blood 88: 3589, 1996).

The disease may be inherited, OR one or more liver problems may cause sufficient deficiency of the enzyme to create an acquired illness. Here's the classification:

• Type I: The gene is normal, but iron overload / alcohol abuse / hepatitis C have damaged the liver enough to produce PCT
• Type II: Inherited deficiency, passed down autosomal-dominant, variably expressed depending on how well one cares for one's liver.
• Type III: Looks like type I, but several people in the same family have it, suggesting a milder allele.

Don't try too hard to sort these out clinically.

Because it usually expresses itself only in the setting of iron overload or chronic liver disease, it is hard to decide where "familial" ends and "multifactorial, like most other diseases" begins.

Unless the deficiency is very severe (the rare, recessive familial PCT), it manifests only if there is also systemic iron overload (i.e., hemochromatosis, older drinkers heterozygous for hemochromatosis, with thal minor, or on dialysis -- Nephron 60: 428, 1992, or with sideroblastic anemia). As you might guess, iron further inhibits the enzyme. The mainstay of treatment is removing iron from the body.

* The plot thickened considerably in 1997, with the discovery that certain hemochromatosis MCH-I alleles produced lots of PCT, and others didn't: Lancet 349: 1025, 1997; Blood 95: 1565, 2000. Puzzle that one out. Chloroquine is available but doesn't work well for the very iron-overloaded: Arch. Derm. 139: 309, 2003 -- anyway, wouldn't you rather have twice-a-week phlebotomy than take medication?

Alcohol also inhibits the enzyme, and acute episodes often follow a drunken spree.

Still other patients have smoldering hepatitis C (South. Med. J. 90: 872, 1997) and/or HIV infections as the trigger (Arch. Derm. 132: 1448, 1996; even in the absence of sickness, HIV often raises the urine and stool levels of porphyrins as in PCT (Arch. Derm. 132: 1443, 1996). Review: Mayo Clin. Proc. 73: 895, 1998. I'd suggest screening all your young PCT patients.

* Aluminum, in old-time uremic patients on dialysis, also caused PCT.

Cool finding: The urine is likely to be reddish or brownish, and if you have a fluorescent light handy, it will glow pink. There's a lot of PCT out there, and the fluorescent light trick will make you look and feel clever. (See Postgrad. Med. 105: 208, 1999).

{12141} porphyria cutanea tarda

Porphyria cutanea tarda Skin, urine NEJM Images with discussion

Porphyria cutanea tarda
Typical hand
U. of Utah

* Future pathologists: Liver biopsy specimens from patients with this disease are fluorescent.

* Homozygous PCT is a more serious disease; you may hear it called "hepatoerythropoietic porphyria". Assaying the enzyme won't tell you which is which, y'gotta examine the patient... Am. J. Med. Sci. 315:59, 1998.

The main problem is SKIN PHOTOSENSITIVITY with increased tanning, blistering, scarring, especially the backs of the hands. There is often hypertrichosis.

The histopathology features separation of epidermis and dermis, without inflammation, and with preservation of the shapes of the dermal papillae. No one really understands how this happens.

The BASIC LAB TEST is URINARY UROPOROPHYRIN. Order it when you see suspicious skin lesions.

Collect this the same way as a sample for porphobilinogen -- ALKALINIZED and PROTECTED FROM LIGHT.

* To screen for latent PCT, there is a test for erythrocyte uroporphyrinogen decarboxylase (Clin. Chem. 34: 2355, 1988).

* Urinary porphobilinogen and delta-amino levulinic acid will be normal.