* 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. 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.

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.

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 are IV hematin (heme hydroxide -- Semin. Hematol. 26: 1, 1989; heme arginate Arch. Int. Med. 153: 2004, 1993;) and glucose. Both inhibit the synthesis of amino-levulinic acid. Consolidate your triumph with tin protoporphyrin (heme oxygenase inhibitor) as follow-up Gastroent. 105: 500, 1993. Liver transplant for cure: Lancet 363: 705, 2004.

VARIEGATE PORPHYRIA

This disease, similar in symptoms to AIP, probably afflicted the European royal families -- King James (Bible Version), George III (American revolution), 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). 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 inherited porphyrias is due to a partial deficiency of uroporphyrinogen decarboxylase. (Molecular biology: Blood 88: 3589, 1996).

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

*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 basic lab test for PCT is urinary uroporphyrin. 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.

(ERYTHROPOIETIC) PROTOPORPHYRIA

Deficiency of ferrochelatase, the enzyme that inserts iron into the completed heme ring. The troublesome allele identified: Blood 93: 2105, 1999; how the mutations work Blood 96: 1545, 2000.

Protoporphyria is rather common and of variable expressivity.

This is primarily a photosensitivity syndrome, with beta-carotene the mainstay of treatment.

A minority get liver damage (sometimes even cirrhosis) from porphyrin crystals which accumulate in the hepatic parenchyma. (Successful transplant: Gastroenterology 98: 816, 1988. Remember this does not cure the disease, and can make it worse -- how? See Gastroent. 100: 1753, 1991.)

* Eventually you can have enough increase in porphobilinogen (or whatever causes the neuropathy of porphyria) to produce a neuropathy: Neurology 51: 262, 1998.

An easy way to help make the diagnosis is by noting the red fluorescence of the erythrocytes.

CONGENITAL ERYTHROPOIETIC PORPHYRIA (* Gunther's disease)

This a rare autosomal recessive disorder with a lack of uroporphyrinogen III synthetase. Gene cloned: Hum. Genet. 88: 320, 1992; molecular biology J. Clin. Inv. 107: 753, 2001; forme fruste Arch. Derm. 128: 1243, 1992.

There are crystals in RBC's which cause hemolysis. The most severe forms might have given rise to stories about vampires and werewolves:



Patients have extreme photosensitivity. Exposure to visible light hurts the eyes and results in hideous mutilation of the skin. Patients avoid daylight.

The patient's face and extremities are abnormally hairy, often strikingly so.

The teeth are red and are fluorescent.

Symptoms could probably be relieved by ingesting heme (i.e., drinking blood).

Dracula and his friends might have felt better on a regular diet of charcoal (NEJM 316: 390, 1987) and carrots (beta-carotene). See also Dragon 131: 8, 1988.

Consider additional factors behind the stories. Violent behavior transmitted by bite: Rabies. "Fresh" blood on the mouth and in the throat of a corpse following burial: Bloody purge of decomposition. The normal slippage of the epidermis after death, described in some exhumation accounts, was interpreted as the vampire shedding its skin like a snake to regain its strength. The groan emitted by the corpse when it was "staked" was escaping gases of decomposition.

* Bone marrow transplantation is curative: J. Ped. 129: 453, 1996; Blood 92: 4053, 1998. Gene therapy cures a tissue culture: Blood 85: 1449, 1995.

ACQUIRED PORPHYRIAS AND PSEUDOPORPHYRIAS

The most important "acquired porphyria" is lead poisoning, which simulates acute intermittent porphyria (abdominal pain, insanity, etc). Lead ion inhibits delta-amino levulinic acid dehydratase (Am. J. Ind. Med. 32: 15, 1997), ferrochelatase (the enzyme that puts the iron into the heme ring when it is finished), and other enzymes.

Looking for low delta-amino levulinic acid dehydratase levels in erythrocytes is probably the best screening test for lead poisoning today.

Erythrocyte zinc protoporphyrin (increased) and urinary delta-amino levulinic acid (increased) are also useful, sensitive procedures.

If you want to collect a specimen for direct assay of atomic lead, ask the lab about special lead-free containers.

Industrial poisons (notably polychlorinated benzene: Arch. Env. Health 54: 248, 1999) have caused and will cause outbreaks of acquired porphyria by interfering with heme metabolism.

The worst was "turkish porphyria" (1954-1959). Seed grain treated with hexachlorobenzene ended up getting eaten instead. Worst-affected were children of nursing mothers; all died. Follow-up: Arch. Neuro. 39: 744, 1982.

As you might expect, the iron chelator desferrioxamine produces an acute porphyria.

A host of photosensitizing drugs cause a rash like that of PCT ("pseudo-porphyria" or the badly-named "acquired PCT") in "predisposed" people. Lab porphyrin and enzyme values remain normal.

Often, a medication will produce a symptom complex similar to PCT; this is "pseudoporphyria" and may be hard to reverse even after discontinuation of the offending medicine (Mayo Clin. Proc. 76: 488, 2001).

REMEMBER: Acute intermittent porphyria can simulate most neurologic and psychiatric diseases, including "drug-seeking malingerers" complaining of atypical pain.

* Anesthesia for the porphyria patient: Anesth. Analg. 80: 591, 1995; gabapentin for seizures seems safe Neurology 46: 1497, 1996.

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Teaching Pathology

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