Neurovisceral Porphyrias:
What a Hematologist Needs to Know
Herbert L. Bonkovsky
The acute or inducible hepatic porphyrias comprise
four inherited disorders of heme biosynthesis. They
usually remain asymptomatic for most of the lifespan
of individuals who inherit the specific enzyme deficien-
cies but may cause life-threatening attacks of
neurovisceral symptoms. Failure to consider the
diagnosis frequently delays effective treatment, and
inappropriate diagnostic tests and/or mistaken
interpretation of results may lead to misdiagnosis and
inappropriate treatment. The four disorders are ALA
dehydratase deficiency porphyria, acute intermittent
porphyria, hereditary coproporphyria, and variegate
porphyria. Other conditions that clinically and bio-
chemically may mimic acute porphyria include lead
The Pathway of Heme Biosynthesis
Each of the porphyrias is due to the deficiency of a specific
enzyme involved in heme synthesis. The normal pathway
of heme synthesis is shown in Figure 1. The first and nor-
mally rate-controlling step is condensation of glycine and
succinyl CoA to form 5-aminolevulinate (ALA), catalyzed
by the mitochondrial enzyme ALA synthase. There are two
forms of ALA synthase, the ubiquitous housekeeping form
1 and the erythroid-specific form 2. These two forms are
products of separate genes and are under quite different
regulation. ALA synthase-1 can be upregulated markedly
by transcriptional and post-transcriptional mechanisms, and
an “uncontrolled” upregulation of this enzyme in the liver
is believed to be the biochemical sine qua non of acute
porphyric attacks. Upregulation of ALA synthase-1 occurs
due to three main known causes:
1. Lipophilic drugs and chemicals, that interact with
nuclear receptors and that, in turn, increase activation
of drug-response elements (RES) in the upstream en-
hancer of ALA synthase-1.1
2. Deficiency of glucose or other gluconeogenic com-
Correspondence: Herbert L. Bonkovsky, MD, The Liver-Biliary-
Pancreatic Center, University of Connecticut, MC-1111, 263
Farmington Avenue, Farmington CT 06030; Phone (860)679-
3759, Fax (860)679-1931, bonkovsky@uchc.edu
Acknowledgments: I thank Jean Clark for help with assembling
and preparing the manuscript.
Grant Support: Supported by NIH grants 1RO1-DK38825;
MO1-RR01692 and NIH contracts NO1-DK92326, and U01-
DK065193.
24
poisoning and hereditary tyrosinemia type I. The
diagnosis of one of these acute porphyric syndromes
should be considered in many patients with otherwise
unexplained abdominal pain, severe constipation,
systemic arterial hypertension, or other characteristic
symptoms. Critical to the rapid diagnosis of the three
most common of these disorders is demonstration of
markedly increased urinary porphobilinogen (PBG) in
a single-void urine specimen. The treatment of choice
for all but mild attacks of the acute porphyrias is
intravenous hemin therapy, which should be started as
soon as possible. Intravenous glucose alone is
recommended only for mild attacks (no weakness or
hyponatremia) or until hemin is available.
pounds that suppress gene expression of ALA syn-
thase-1 (the so-called “glucose effect”2).
3. Deficiency of heme, the end-product of heme pathway
shown in Figure 1, which not only represses transcrip-
tion of the ALA synthase-1 gene,2 but also blocks trans-
location of the enzyme into mitochondria and decreases
the stability of its mRNA.3,4
Downregulation of ALA synthase-1 by avoidance or re-
moval of inducing drugs and chemicals by nutritional means
(high carbohydrate intakes) and by administration of ex-
ogenous heme remains the cornerstone of management of
the acute porphyrias.
As shown in Figure 1, there is no porphyria associated
with a defect in ALA synthase-1, but mutations of the X-
linked ALA synthase-2 (the erythroid form) are causative
for X-linked sideroblastic anemia. Indeed, one would ex-
pect the opposite, namely inadequate porphyrin synthesis,
if this enzyme were markedly deficient in activity. It is
highly unlikely that such defects would be compatible with
life. The other enzymes, when deficient, give rise to the
types of porphyrias shown in Tables 1 and 2. The last three
enzymes of the pathway, namely, coproporphyrinogen III
oxidase, protoporphyrinogen oxidase, and ferrochelatase,
are also located within mitochondria, whereas the 2nd–5th
enzymes are found in the cytoplasm or soluble fraction of
the cell.
Classification of the Porphyrias
The porphyrias are usually classified as either hepatic or
erythropoietic based on the principal site of expression of
the enzymatic defect (Table 1). All of the acute or induc-
ible hepatic porphyrias (5-aminolevulinate dehydratase de-
American Society of Hematology
Figure 1. Heme biosynthetic pathway showing the sites of enzymatic defects in the porphyrias and the major biochemical
abnormalities in biochemically active disease. Only the major increases in the urine, stool, plasma, and erythrocytes (RBCs) are
shown. The dashes (—) represent no abnormalities. For several of the diseases, many patients are biochemically silent (“latent”)
carriers of the enzymatic defects for most of their lives.
Abbreviations: COPRO, coproporphyrin; COPROGEN, coproporphyrinogen; ISOCOPRO, isocoproporphyrin; PROTO,
protoporphyrin; URO, uroporphyrin; UROGEN, uroporphyrinogen; Zn, zinc.
Reprinted with permission from Chemmanur AT, Bonkovsky HL. Hepatic porphyrias: diagnosis and management. Clin Liver Dis.
2004;8:807-838.

ficiency porphyria [ADP], acute intermittent porphyria
[AIP]; hereditary coproporphyria [HCP], and variegate por-
phyria [VP]) are hepatic as are the porphyrias associated
with deficiency of uroporphyrinogen decarboxylase,
namely porphyria cutanea tarda and hepatoerythropoietic
porphyria. The erythropoietic forms are congenital eryth-
ropoietic porphyria or Gunther’s disease and erythropoi-
etic protoporphyria. Erythroid cells contribute significant
amounts of porphyrins in hepato-erythropoietic porphy-
ria, so this form of porphyria may be considered as both a
hepatic and an erythropoietic type of porphyria. The major
clinical features of the individual porphyrias are summa-
rized in Table 1. They consist of attacks of neurovisceral
symptoms and cutaneous manifestations. In some forms,
liver damage may also occur and an increased risk of hepa-
tocellular carcinoma. This risk is increased in porphyria
cutanea tarda, hepatoerythropoietic porphyria, and in all
of the acute hepatic porphyrias, as well as in erythropoietic
protoporphyria. The remainder of this overview will be lim-
ited to discussion of the four acute porphyrias. Their ge-
netic and enzymatic features are summarized in Table 2.
Pathogenesis of Acute Attacks
As shown in Table 2, the enzyme deficiencies are partial
(usually about 50% of normal in three of the acute porphyrias
and usually less than 5% of normal in the fourth [ADP]),
and the residual enzymatic activity is usually sufficient to
maintain adequate hepatic heme synthesis. Activity of ALA
dehydratase normally greatly exceeds that of the other en-
zymes of the heme biosynthetic pathway in the liver. There-
fore, a much more severe deficiency in the activity of this
enzyme (less than 5% of normal) is usually needed to cause
manifestations of ALA dehydratase deficiency porphyria.
Such enzymatic defects are envisioned to predispose af-
fected persons to the deleterious influences of factors that
may trigger acute attacks, including drugs, such as barbitu-
rates, hydantoins, rifampin, progestins, endogenous steroid
hormones (especially progesterone), prolonged severe fast-
ing or dieting, alcohol, and other intercurrent illnesses or
stress. All of these can either increase the demand for he-
patic heme or otherwise reduce the regulatory pool for heme
and thus induce or upregulate synthesis of ALA synthase
(shown in Figure 2). Because hepatic ALA synthase-1 is
normally rate-controlling, when production of heme path-
way intermediates increases, the inherited partial enzymatic
deficiency more distal in the pathway becomes rate limit-
ing, and proximal intermediates accumulate. For reasons
that are complex and not fully understood, intermediates
distal to the inherited enzyme deficiency or their products
may also accumulate.
Although the precise pathogenic mechanisms under-
lying the neurologic damage in the acute porphyrias re-
main imperfectly understood, it seems likely that symp-
toms result primarily from accumulation of the porphyrin
precursors, rather than deficiency of heme in nerve or muscle
tissue.5,6 Symptomatic acute porphyria rarely becomes clini-
cally manifest prior to puberty (highlighting the impor-
tance of endogenous steroid hormones, especially proges-
terone and less so estrogens), and the disease is more often
clinically manifested in women, often with cyclical attacks
linked to menstrual cycles. Very rare instances of homozy-
gous acute porphyria with severe neurologic manifestations

Hematology 2005 25
Table 1A. Classification of the porphyrias.

1. According to Sites of Major Overproduction of

Porphyrins and Porphyrin Precursors

Erythropoietic Hepatic
CEP Acute, Inducible
EPP ADP
AIP
HCP
VP
Chronic
PCT
HEP

2. According to Major Clinical Manifestations

Abdominal pain Cutaneous
(neurovisceral) (photosensitivity, damage)
ADP CEP
AIP EPP
HCP HCP Figure 2: Regulation of the hepatic heme biosynthetic
VP HEP pathway and subcellular localization of the enzymes of
PCT the pathway.
VP Schematic of the synthesis of heme and its regulation. The
Abbreviations: CEP, congenital erythropoietic (Uro) porphyria; regulatory heme pool acts to stimulate (+) or down-regulate (–)
EP, erythropoietic protoporphyria; ADP, ALA dehydratase the indicated steps. Those steps indicated as not within the
deficiency porphyia; AIP, acute intermittent porphyria; HCP, nucleus or mitochondrion take place in the cytosol. The dashed
hereditary coproporphyria; VP, variegate porphyria; PCT, line indicates a still controversial regulatory effect of heme to
porphyria cutanea tarda; HEP, hepato-erythropoietic porphyria. decrease transcription of the gene of ALA synthase 1.
Abbreviations: ALA, 5-aminolevulinate; CO, carbon monoxide;
Table 1B. Summary of major clinical features of the CoA, coenzyme A; PBG, porphobilinogen.
porphyrias. Reprinted from Chemmanur AT, Bonkovsky HL. Hepatic
porphyrias: diagnosis and management. Clin Liver Dis.
2004;8:807-838, with permission from Elsevier.
Type of Neuro- Clinical Manifestation
Porphyria visceral Cutaneous Liver Damage
ADP Yes No No
beginning in childhood have been described.5,7,8 Perhaps
AIP Yes No No
the most persuasive evidence that overproduction of he-
HCP Yes Yes (bullae, fragility) No
patic ALA and/or porphobilinogen (PBG) are central is the
VP Yes Yes (bullae, fragility) No
clinical observation of their unique association with dis-
PCT No Yes (bullae, fragility) Yes eases that present with neurovisceral attacks. Further evi-
HEP +/– Yes (bullae, fragility) Yes dence was the rapid and dramatic improvement in chronic
CEP No Yes (bullae, fragility) Occasional debilitating neurovisceral attacks that occurred following
EPP Rarely* Yes (urticaria, erythema) Yes (10%) liver transplantation in a young woman with AIP.6 A pa-
tient with a diagnosis of variegate porphyria, who under-
The porphyrias are listed with respect to their dominant went liver transplantation for alcoholic cirrhosis, similarly
symptoms with neurovisceral or cutaneous manifestations and experienced biochemical improvement after liver trans-
the presence of potential liver damage. plantation.9 In contrast, liver transplantation was not ben-
Reprinted from Chemmanur AT, Bonkovsky HL. Hepatic
porphyrias: diagnosis and management. Clin Liver Dis. eficial clinically or biochemically in a child with severe
2004;8:807-838, with permission from Elsevier. ALA dehydratase deficiency, suggesting that ALA over-
Abbreviations: ADP, ALA dehydratase deficiency porphyria; AIP, production did not arise chiefly from the patient’s native
acute intermittent porphyria; ALA, 5-aminolevulinate; CEP, liver.10
congenital erythorpoietic porphyria; EPP, erythorpoietic
protoporphyria; HCP, hereditary coproporphyria; HEP,
hepatoerythrocytic porphyria; PCT, porphyria cutanea tarda; VP, Common Clinical Features
variegate porphyria The most common presenting symptom of acute porphyria
* EPP with end-stage liver disease, especially just after liver is abdominal pain. This is usually colicky in nature and in
transplantation, may rarely be associated with neurovisceral
manifestations. the lower abdomen. It lasts hours to days. The most com-
mon sign in acute porphyric attacks is tachycardia. Table 3
lists other common presenting symptoms and signs with
estimates of incidence and other comments. Among neuro-
logic manifestations, evidence of autonomic neuropathy

26 American Society of Hematology

Table 2. Genetic and enzymatic features of the acute hepatic porphyrias.

Deficient Enzymes
Disease Inheritance (Synonyms; Sequence Subcellular Enzyme Activity Known Gene
(Abbreviation) Number‡ in Pathway) Locations % of normal Mutations, n† Locus OMIM
Acute intermittent Autosomal PBG deaminase (HMB Cytosolic ~ 50 227 11q23.3 176000
porphyria (AIP) dominant synthase; third)§
Hereditary Autosomal Coproporphyrinogen Mitochondrial ~ 50 36 3q12 +121300
coproporphyria dominant oxidase (sixth)
Variegate porphyria Autosomal Protoporphyrinogen Mitochondrial ~ 50 120 1q22 #176200
(VP) dominant oxidase (seventh)
ALA-dehydratase Autosomal ALA dehydratase Cytosolic ~5 7 9q34 +125270
deficient porphyria recessive (porphobilinogen
(ADP) syntase; second)

* Acute intermittent porphyria is the most prevalent and 5-aminolevulinic acid-dehydratase deficient porphyria is the least prevalent of
these diseases in the United States.
Abbreviations: ALA, 5-aminolevulinic acid (d-aminolevulinic acid); HMB, hydroxymethylbilane; OMIM, Online Mendelian Inheritance in
Man; PBG, porphobilinogen.
† Human Gene Mutation Database (www.hgmd.org) as of 14 October 2004.
‡ Online Mendelian Inheritance in Man (for additional information on disease and its genetics) (www.ncbi.nlm.nih.gov/entrez/
query.fcgi?db=OMIM)
§ Formerly known as uroporphyrinogen I synthase.
Reprinted with permission from Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment
of the acute porphyrias. Ann Intern Med. 2005;142:439-450.

with a sympathomimetic state characterized by tachycar- Neuropsychiatric manifestations of anxiety, depression,

dia and systemic arterial hypertension is most common.
Severe constipation is also very common. Peripheral neur-
opathy, which is predominantly a motor neuropathy, ini-
tially affecting mainly the proximal rather than distal
muscles, is next in order of frequency. Sensory loss over the
trunk is also common, although it is often overlooked.
insomnia, disorientation, hallucinations, and paranoia oc-
cur somewhat less commonly as do cranial nerve defects,
seizures, or coma, and cerebellar, optic nerve, basal gan-
glion or pyramidal tract involvement. Another common
manifestation is hyponatremia, which is usually due to
vomiting and replacement of fluid lost with hypotonic so-

Table 3. Common symptoms and signs of acute porphyria.

Estimated
Symptoms and Signs Incidence, % Comment
Gastrointestinal
Abdominal pain 85-95 Usually unremitting (for hours or longer) and poorly localized but can be cramping.
Neurologic in origin and rarely accompanied by peritoneal signs, fever, or leukocytosis.
Vomiting 43-88 Nausea and vomiting often accompany abdominal pain.
Constipation 48-84 May be accompanied by bladder paresis.
Diarrhea 5-12
Neurologic
Pain in extremities, back, 50-70 Pain may begin in the chest or back and move to the abdomen. Extremity pain
chest, neck, or head indicates involvement of sensory nerves, with objective sensory loss reported in
10%-40% of cases.
Paresis 42-68 May occur early or late during a severe attack. Muscle weakness usually begins
proximally rather than distally and more often in the upper than lower extremities.
Respiratory paralysis 9-20 Preceded by progressive peripheral motor neuropathy and paresis.
Mental symptoms 40-58 May range from minor behavioral changes to agitation, confusion, hallucinations, and
depression.
Convulsions 10-20 A central neurologic manifestation of porphyria or due to hyponatremia, which often
results from syndrome of inappropriate antidiuretic hormone secretion or sodium
depletion.
Cardiovascular
Tachycardia 64-85 May warrant treatment ot control rate, if symptomatic (see text).
Systemic arterial 36-55 May require treatment during acute attacks, and sometimes becomes chronic.
hypertension

Reprinted with permission from Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment
of the acute porphyrias. Ann Intern Med. 2005;142:439-450.

Hematology 2005 27
lutions such as intravenous glucose without electrolytes,
and to excessive secretion of antidiuretic hormone. Al-
though it is often said that this represents inappropriate
secretion of antidiuretic hormone, when plasma and blood
volumes of patients with acute porphyria were measured,
they were found to be decreased.11 In the setting of plasma
volume depletion, secretion of antidiuretic hormone can
not truly be said to be inappropriate. Sudden death, prob-
ably due to cardiac arrhythmia, may occur during acute
attacks.12 Death can also be a consequence of progressive
paralysis, including paralysis of respiratory muscles and
bulbar paralysis with complicating disorders such as
pneumonias and aspiration.
Recommendations for Diagnosis
It is important that the diagnosis of acute porphyria be
considered early on when patients present to the emergency
room or other urgent care settings with compatible symp-
toms and signs. Too often, acute porphyria is considered
only after expensive, time-consuming, unproductive
searches for other causes of abdominal complaints have
been carried out, sometimes including ill-advised and un-
necessary surgery. Careful personal history may reveal re-
current episodes of colicky, usually lower, abdominal pain
lasting for hours to days with associated obstipation. ER
records of tachycardia and systemic arterial hypertension
provide helpful clues. Attacks that occur cyclically in men-
struating women, with onset during the bruited phase of
the menstrual cycle, are suggestive, although more likely
due to endometriosis than acute porphyrias. Severe stress,
starvation, “crash” dieting, alcohol excess, or intercurrent
infections may trigger acute porphyric attacks. A positive
family history of porphyria, if established at a reputable
center, is important, although usually not elicited.
The key to establishing or excluding the diagnosis is
rapid and simple testing for increased porphobilinogen
(PBG) in the urine. This should be done in a single freshly
passed urine to which no preservatives are added. Classi-
cally, the qualitative test for PBG in the urine has been the
Watson-Schwartz test, although the Hoesch test is also use-
ful and may be less prone to misinterpretation.13 The com-
mercially available Trace PBG kit (Trace American/Trace
Diagnostics, Louisville, Colorado) is useful and includes a
color chart for semi-quantitative estimation of levels of
urinary PBG. These levels are generally markedly increased
(20-200 mg or 220-880 µmol/day with a typical reference
range of 0-4 mg or 0-18 µmol/day). In all cases of acute
porphyric syndromes except for the very rare porphyria
due to ALA dehydratase deficiency or in patients with symp-
toms due to lead poisoning or hereditary tyrosinemia type
I, markedly elevated urinary porphobilinogen is expected
and readily detectable. If the porphobilinogen level is in-
creased, second line testing including erythrocytic PBG
deaminase levels, urinary, fecal, and plasma porphyrin lev-
els will establish the precise disorder of porphyrin metabo-
lism (Table 4). The most useful tests are the erythrocytic
PBG deaminase level for AIP, the urine and fecal porphyrin
levels for HCP, and the plasma porphyrin level and fluores-
cence pattern for VP. Worthy of emphasis is that about 10%
of patients with AIP have normal erythrocytic PBG deami-
nase levels. There is a single gene encoding PBG deami-
nase, but erythroid cells utilize different promoters and tran-
scriptional sites than hepatocytes and other cells. As a re-
sult, the erythrocyte enzyme lacks the amino terminal resi-
dues encoded by exon 1. Therefore, in the 10% or so of
patients with AIP who have mutations in exon 1, erythro-
cytic PBG deaminase activities are entirely normal. An-
other limitation is that there is a large range of variation in
activity of the enzyme, and there is an overlap between
normals and carriers of the deficiency.

Table 4. Laboratory findings that differentiate acute intermittent porphyria, hereditary coproporphyria, and variegate
porphyria.*

Erythrocyte
Porphobilinogen Urine Fecal Plasma
Disease Deaminase Levels Porphyrin Levels Porphyrin Levels Porphyrin Levels
Acute intermittent Decreased by ~ 50% Increased, Normal or Normal or
porphyria (in ~ 90% of cases) mostly uroporphyrin slightly increased slightly increased
Hereditary Normal Increased, mostly Increased, mostly Usually normal
coproporphyria coproporphyrin coproporphyrin†
Variegate porphyria Normal Increased, mostly Increased, mostly Increased,
coproporphyrin coproporphyrin† and characteristic
protoporphyrin fluorescence peak‡

Reprinted with permission from Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment
of the acute porphyrias. Ann Intern Med. 2005;142:439-450.
* The findings listed are considered diagnostic for acute intermittent porphyria when porphobilinogen level is increased and for
hereditary coproporphyria and variegate porphyria even when porphobilinogen levels may have returned to normal.
† Mostly coproporphyrin III
‡ A simple test, which consists of fluorescence scanning of diluted plasma at neutral pH, readily differentiates variegate porphyria
from other porphyrias that cause elevated plasma porphyrin levels and cutaneous photosensitivity. A plasma porphyrin level
determination is the most sensitive porphyrin measurement for detecting variegate porphyria, including asymptomatic cases.

28 American Society of Hematology

 Diagnosis of ALA dehydratase deficiency, in which
PBG is normal or only slightly increased, requires mea-
surement of urinary ALA, which can be done on the same
urine sample. Associated findings include elevations in
urinary coproporphyrin and erythrocyte Zn protoporphy-
rin and markedly deficient erythrocyte ALA dehydratase
activity. Other causes of this enzyme deficiency must be
excluded.
After the above first- and second-line biochemical stud-
ies have established the presence and type of acute por-
phyria, DNA studies can identify the disease-causing mu-
tation or mutations in the defective gene. Demonstration
of a mutation in each ALA dehydratase allele is important
for confirming the diagnosis of porphyria due to ALA
dehydratase deficiency. If a mutation has been found in a
proband, rapid and accurate testing of asymptomatic-at-
risk family members can be carried out. DNA-based studies
are rather widely available in European counties at central,
government supported laboratories. Mutational analysis
for patients and family members with acute porphyria in
the United States is currently available through the Depart-
ment of Human Genetics, Mt. Sinai School of Medicine,
New York, NY (contact Dr. Kenneth Astrin for information
at kenneth.astrin@mssm.edu).
Recommendations for Management
Key principles of management are summarized in Table 5.
Removal of inciting factors, such as one of the many drugs
or chemicals that can trigger or exacerbate acute porphyrias,
is essential. Nutritional supplementation, including at least
300 g of glucose given daily, is important because glucose
suppresses activity of ALA synthase-1.14 Due to nausea,
vomiting, disordered bowel motility, etc., such supplemen-
tal glucose usually must be administered intravenously.
Because of the danger of severe hyponatremia, sodium
should be administered and levels of serum sodium should
be monitored frequently. There should also be frequent
checks of neurological status, especially looking for evi-
dence of the development of impairment of swallowing,
coughing, and respiration. Prompt transfer to an intensive
care unit for close monitoring and provision of respiratory
support and other intensive nursing care may be life saving.
Table 5. Therapy of acute attacks of porphyria.
• Remove inciting factors: alcohol, drugs, toxins, chemicals
• Nutritional supplementation: at least 300 grams glucose/day
• Frequent checks of neurologic status: especially watch for
development of paresis of muscles of respiration
• Monitor for hypoventilation (rising arterial PpCO2), hyponatre-
mia, or hypomagnesemia and treat vigorously if found
• Intravenous heme: 3-4 mg/kg/day for 3-5 days
• Parenteral meperidine or morphine for pain
• Phenothiazines for nausea, vomiting, agitation, etc.
• Propranolol or nadolol for tachycardia, hypertension
Hematology 2005
Tachycardia and/or systemic arterial hypertension can
be treated cautiously with beta-adrenergic blocking agents
such as propranolol or nadolol. Typical daily doses are 40-
240 mg of propranolol or 60-120 mg of nadolol. Caution
must be exercised when using beta blockers because hy-
potension and serious bradycardia have been reported even
after low doses.15 Analgesia in the form of parenteral ad-
ministration of morphine (3-12 mg/dose or meperidine 50-
200 mg/dose) is recommended, because these agents have
been found to be safe and effective. Such analgesics may
depress respiratory drive, such that monitoring of respira-
tory adequacy (e.g., arterial blood gases) is important.
Addition of a phenothiazine (e.g., chlorpromazine, 10-
15 mg/dose) enhances the analgesic and sedative effects of
narcotics and helps to treat the agitation and anxiety that
often accompany acute porphyric attacks, and are also ef-
fective for nausea and vomiting. If seizures supervene, the
treatments of choice are benzodiazepines, gabapentin, and
vigabatrin. Hyponatremia and hypomagnesemia should be
corrected.
Hemin Therapy
Intravenous hemin (the generic term for both heme prod-
ucts marketed for intravenous use), given as quickly as it
can be obtained, is the treatment of choice for any patient
who is ill enough to require hospital admission for acute
porphyria. The standard regimen for hemin therapy is 3-4
mg/kg/day for 3-5 days. In the United States, hemin in the
form of Panhematin (Ovation Pharmaceuticals, Deerfield,
IL) is the only preparation available. Although the product
labeling recommends an initial trial of intravenous glu-
cose, heme should be given without delay. Lyophilized
hematin should be reconstituted with human serum albu-
min to enhance its stability.16 In addition to minimizing
the formation of polymers and other degradation products
that form rapidly when hematin is reconstituted with ster-
ile water (as currently recommended in product labeling),
there are lesser adverse effects on coagulation and irrita-
tion to veins (phlebitis, etc.). Heme arginate, which is ap-
proved in many other countries, is stable in concentrated
solution and somewhat less irritating to veins, although it,
too, is commonly given with human serum albumin.
Recommendations for Prevention and Follow-up
All patients with acute porphyria should carry Medic Alert
bracelets and wallet cards, as well as a list of safe and un-
safe drugs, so that these are readily available to emergency
response personnel in the event of accident or incapacity.
For women with frequent cyclical attacks, use of gonado-
tropin-releasing hormone (GNRH) analogs is frequently
highly effective. Other women have benefited from the use
of low-dose estrogen and progesterone such as in low-dose
birth control pills or estrogen patches. Estrogen patches
can also be used to help prevent menopausal symptoms in
women receiving GNRH analogs. Although pregnancy pro-
duces increased levels of progesterone, most women with
29
acute porphyria tolerate pregnancy remarkably well.
Some patients, most of them women with cyclical at-
tacks, seem to require and benefit from regular prophylac-
tic infusions of hemin. These may be given only once a
month, shortly before the usual onset of symptoms, or they
may be administered weekly or biweekly, especially if the
attacks are frequent and mostly unrelated to the cycle. The
frequency and doses used are empiric and dependent chiefly
upon the symptoms of the patient.
Because of the increased risk of development of hepa-
tocellular carcinoma (HCC) in the hepatic porphyrias, it is
becoming more common to do surveillance screening for
HCC in affected persons. This is usually done with semian-
nual serum alphafetoprotein and liver ultrasound (perhaps,
alternating with 4-phase, helical, dynamic CT scan). The
cost-effectiveness of such surveillance is not established,
but the practice has gained in popularity nonetheless.
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