Acute Porphyria 

Updated: Nov 22, 2019
Author: Richard E Frye, MD, PhD; Chief Editor: Lawrence C Wolfe, MD 

Overview

Background

The porphyrias are caused by enzyme deficiencies in the heme production pathway.[1, 2] Such deficiencies may be due to inborn errors of metabolism or exposure to environmental toxins or infectious agents. Because of the ubiquitous use of heme in the human body, severe enzyme deficiencies are lethal. See the image below.

Heme production pathway. Heme production begins in Heme production pathway. Heme production begins in the mitochondria, proceeds into the cytoplasm, and resumes in the mitochondria for the final steps. Figure outlines the enzymes and intermediates involved in the porphyrias. Names of enzymes are presented in the boxes; names of the intermediates, outside the boxes. Multiple arrows leading to a box demonstrate that multiple intermediates are required as substrates for the enzyme to produce 1 product.

Many genetic defects result in porphyria. Variable penetrance is the rule. In most cases, concomitant environmental and genetic factors are required to produce phenotypic symptoms, though the exact nature of such factors is unknown.

Porphyrias are divided into acute and cutaneous categories based on their predominant symptoms. Patients with acute porphyrias (ie, neurovisceral porphyria) present with symptoms of abdominal pain, neuropathy, autonomic instability, and psychosis. Cutaneous porphyrias cause photosensitive lesions on the skin. Aminolevulinic acid dehydratase (ALAD) deficiency and acute intermittent porphyria (AIP) cause predominately neurovisceral symptoms, whereas congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP) mainly cause cutaneous symptoms. Hereditary coproporphyria (HCP) and variegate porphyria (VP) cause both acute and cutaneous symptoms.

This article addresses only the acute porphyrias. For information on the diagnosis and management of cutaneous porphyrias and cutaneous manifestations of porphyrias with neurovisceral and cutaneous components, see Porphyria, Cutaneous. This division is aimed at presenting these disorders in an easily understandable format.

Some of the confusion regarding the porphyrias is derived from the many synonyms for each particular disorder.

Synonyms associated with the various types of acute porphyria are as follows:

Aminolevulinic acid dehydratase

See the list below:

  • ALAD Deficiency

  • Porphobilinogen (PBG) synthase deficiency

  • Aminolevulinic acid (ALA) dehydrase deficiency

  • ALA-uria

  • Doss porphyria

Acute intermittent porphyria

See the list below:

  • Hydroxymethylbilane synthase deficiency[3, 4]

  • Intermittent acute porphyria

  • Waldenstrom porphyria

  • Pyrroloporphyria

Hereditary coproporphyria

See the list below:

  • Coproporphyria

  • Coproporphyrinogen oxidase deficiency

Variegate porphyria

See the list below:

  • Protoporphyrinogen oxidase deficiency

  • South African porphyria

  • Porphyria variegata

  • Protocoproporphyria hereditaria

Pathophysiology

Porphyrin pathway

Heme is an essential physiologic compound. It is critical for oxygen binding and transport, for the cytochrome P-450 pathway, for activation and decomposition of hydrogen peroxide, for oxidation of tryptophan and prostaglandins, and for the production of cyclic guanine monophosphate (cGMP). The liver produces approximately 15% of the body's heme; bone marrow produces the remainder. Heme produced in the liver is primarily used for cytochromes and peroxisomes, whereas heme produced in the bone marrow is used primarily for oxygen transport. Biosynthesis of 1 heme molecule requires 8 molecules of glycine and succinyl-coenzyme A (CoA).[5]

Enzymes required for the biosynthesis of heme are located in the mitochondria or the cytosol.

Table 1. Known Chromosomal Location of Enzymes Involved in Porphyria and Inheritance Patterns (Open Table in a new window)

Type of Porphyria

Deficient Enzyme

Location

Inheritance Pattern

Band

 

ALAD deficiency

ALAD

Cytosol

Autosomal recessive

9q34

 

AIP

PBG deaminase

Cytosol

Autosomal dominant

11q23

 

HCP

Coproporphyrinogen oxidase

Mitochondrial

Autosomal dominant

3q12

 

VP

Protoporphyrinogen oxidase

Mitochondrial

Autosomal dominant

1q22-23

 

As the first step in the heme biosynthesis pathway, ALA synthase condenses glycine and succinyl-CoA. This enzyme has 2 isoforms encoded by separate genes; all tissues express the housekeeping isoform, whereas only hematologic tissue express the erythroid isoform. ALA synthase is the rate-limiting step for heme production in the liver but not in the bone marrow. The erythron responds to stimuli for heme synthesis by increasing cell number. In the liver, ALA synthase and PBG deaminase are normally at low levels, resulting in ALA and PBG accumulation with increased ALA production under normal conditions. High ALA levels induce heme oxygenase, increase bilirubin production, and inhibit ALA synthase.

Heme inhibits ALA synthase synthesis, mitochondrial transfer, and catalytic activity. These inhibitory mechanisms lead to tight control of ALA production since ALA synthase turnover is rapid. Exogenous chemicals can induce ALA synthase in the liver by depleting existing heme or by inhibiting heme synthesis. The 3 common mechanisms are destruction or enhanced production of cytochrome P-450 heme and rapid inhibition of ferrochelatase.

ALAD condenses 2 molecules of ALA to form the monopyrrole PBG. ALAD is inhibited by lead, levulinic acid, hemin, succinylacetone, and alcohol. Lead displaces zinc from the enzyme, but this inhibition can be reversed by administering supplemental zinc or dithiothreitol. Succinylacetone, a substrate analogue of ALA found in patients with hereditary tyrosinemia, is the most potent inhibitor of ALAD.

PBG deaminase catalyzes the polymerization of 4 molecules of PBG, in a head-to-tail orientation, yielding a linear tetrapyrrole intermediate hydroxymethylbilane. The same structural gene encodes tissue and erythrocyte isoenzymes.

Uroporphyrinogen I and III cosynthase form uroporphyrinogen I and III from hydroxymethylbilane cyclizing the linear molecule. Uroporphyrinogen I reverses the orientation of the last pyrrole ring while uroporphyrinogen I does not. Normal tissues contain an excess of uroporphyrinogen cosynthases, compared with PBG deaminase.

Uroporphyrinogen decarboxylase sequentially removes a carboxylic group from the acetic side chains of each of the pyrrole rings to yield coproporphyrinogen. This enzyme has highest affinity for uroporphyrinogen III. Several metals (eg, copper, mercury, platinum) inhibit this enzyme. The effect of iron on this enzyme is not clear.

Coproporphyrinogen oxidase removes a carboxyl group from the propionic groups on 2 of the pyrrole rings to yield protoporphyrinogen IX. Protoporphyrinogen oxidase forms protoporphyrin IX by removing 6 hydrogen atoms from protoporphyrinogen IX. This enzyme has been identified in human fibroblasts, erythrocytes, and leukocytes and is noncompetitively and irreversibly inhibited by hemin. Iron is inserted into protoporphyrin by ferrochelatase as the final step in the heme synthesis pathway. Enzyme activity is stimulated by fatty acids and is inhibited by metals (eg, cobalt, zinc, lead, copper, manganese) and by metalloporphyrins.

Nervous system dysfunction

ALA, PBG, and their derivatives are neurotoxic to central and peripheral nerves. Disturbed heme synthesis in neural tissue results in depletion of essential cofactors and substrates. For example, Schwann cells may be sensitive to damage because they synthesize and use cytochrome P-450. Any disturbance in cytochrome production and function may lead to cell dysfunction and demyelination.

ALA antagonizes the gamma-aminobutyric acid (GABA) receptor and may cause oxidative damage to nervous tissue. Decreased activity of the heme-dependent protein tryptophan pyrrolase in the liver supposedly increases central and systemic tryptophan levels due to decreased tryptophan degradation. Increased central 5-hydroxytryptamine levels may cause cognitive changes.

Chronic renal failure

Chronic renal failure may be caused by a combination of sustained hypertension, analgesic nephropathy, and intermediates in the nephrotoxic porphyrin pathway.

DNA damage

ALA may cause dose-dependent damage to nuclear and mitochondrial DNA.

Epidemiology

Frequency

United States

The absence of a porphyria registry in the United States impedes accurate calculation of disease frequency. Incidence of the acute porphyrias varies with type (see Table 2). The highly variable phenotypic expression results in a highly variable penetrance. Most individuals with the genetic defects are asymptomatic. Therefore, underdiagnosis and variable penetrance contribute to the lack of knowledge about the incidence of acute porphyria.

The proportion of patients with a known PBG deaminase mutation who develop symptoms appears to have decreased substantially after 1980.

International

The frequency of the genetic defects that cause porphyria is unknown. Surveillance studies aimed at symptomatic families may bias genetic defect prevalence. Incidences listed in Table 3 below mitigate surveillance bias. Studies in Finnish and Russian populations indicate that the risk of developing symptoms may be proportional to the specific mutation in AIP.

Table 2. Frequencies of Porphyria (Open Table in a new window)

Type of Porphyria

Age of Onset

Incidence

Male-to-Female Ratio

ALAD deficiency

Mostly adolescence to young adulthood, but variable (2-63 y)

6 cases total

6:0

AIP

After puberty (third decade)

General 0.01/1000

Sweden 1/1000

Finland 2/1000

France 0.3/1000

M>F

HCP

Predominantly adulthood (youngest patient aged 4 y)

Japan 0.015/1000

Czech 0.015/1000

Israel 0.007/1000

Denmark 0.0005/1000

1:20

1:4

2:1

1:1

VP

Heterozygous mutation: after puberty (fourth decade) Homozygous mutation (rare): childhood

South Africa 0.34/1000

1:1

 

Mortality/Morbidity

Mortality is associated with secondary cardiovascular disease, chronic renal failure, and hepatocellular carcinoma. Catecholamine hypersecretion has been implicated in cases of sudden death. Long-term morbidity results from renal damage, hypertension, peripheral neuropathy, and psychiatric disturbances.[6]

A Norwegian study, by Baravelli et al, supported the contention that acute porphyria increases the risk of primary liver cancer (PLC), finding that, in comparison with the reference population, the adjusted hazard ratio for PLC in acute porphyria patients was 108. The investigators also conducted a literature review, which indicated that the risk of acute porphyria–related PLC is greater in women than in men. In addition, the authors found evidence that acute porphyria raises the risk of renal and endometrial cancer.[7]

Race

Certain ethnic groups are predisposed to porphyrias (see Table 2). Individuals of Swedish and Finnish descent have a high prevalence of AIP. Prevalence of VP is particularly high among South Africans of Danish descent.

Sex

The increased prevalence of acute porphyrias in women probably reflects the significant exacerbation by female sex hormones.

Age

Most patients with acute porphyria present after puberty, but the disease can occur in childhood. In female patients, acute porphyria is particularly evident after puberty, but its severity and overall prevalence after menopause. Patients with VP may present later in life than those with AIP.

 

Presentation

History

Recent provoking factors for acute porphyria include the following:

  • Alcohol ingestion

  • Infection

  • Surgical procedure

  • Known provoking drug (see Deterrence/Prevention)

  • Low-carbohydrate diet or fasting

  • Menstruation

Seizures that are difficult to control or that worsen with standard anticonvulsants drug administration

Pregnancy can precipitate hereditary coproporphyria (HCP) but not acute intermittent porphyria (AIP).[8]

Physical

Vital signs

See the list below:

  • High blood pressure and tachycardia during acute attacks

  • Chronic changes (eg, sustained hypertension in 20% of patients)

GI symptoms

See the list below:

  • Abdominal pain

  • Nausea, vomiting

  • Partial ileus with accompanying severe nonfocal abdominal pain

  • Absent peritoneal signs

Neurologic symptoms

Autonomic neuropathy symptoms include the following[9] :

  • Unstable vital signs

  • Excessive sweating

  • Dysuria and bladder dysfunction

  • Fever

  • Restlessness

  • Tremor

  • Catecholamine hypersecretion

Peripheral neuropathy symptoms include the following:

  • Guillain-Barré–like syndrome after prolonged and severe episodes

  • Focal, asymmetric, or symmetric weakness beginning proximally and spreading distally with foot or wrist drop

  • Focal, patchy mild-to-severe paresthesias, numbness, and dysesthesias

  • Tetraplegia (reported in cases of hereditary coproporphyria [HCP])

  • Respiratory paralysis (rare but can occur)

Cranial nerve symptoms include the following:

  • Motor nerve palsies (particularly cranial nerves VII and X)

  • Optic nerve involvement (may lead to blindness)

Seizures symptoms include the following:

  • Seizures are most common during acute attacks.

  • Tonic-clonic (more common) and/or partial (less common) seizures with secondary generalization are most common.

  • The lifetime prevalence of seizures is 4%.

  • The risk of seizure during an acute episode is 5%.

Cortical symptoms are as follows:

  • Encephalopathy

  • Aphasia

  • Apraxia

  • Cortical blindness

Psychiatric symptoms

Acute symptoms include the following:

  • Anxiety

  • Agitation

  • Confusion

  • Depression

  • Hallucinations

  • Insomnia

  • Paranoia

  • Violent behavior

Chronic symptoms include the following:

  • Depression

  • Anxiety

A study by Cederlöf et al indicated that the risk of schizophrenia or bipolar disorder is fourfold higher in persons with acute intermittent porphyria and is twofold higher in first-degree relatives of these individuals. The study included 717 individuals with the disease.[10]

Other symptoms

See the list below:

  • Muscular symptoms (rhabdomyolysis)

  • Urine changes (may turn red or dark when exposed to light)

Causes

Porphyria is considered a genetic disorder. Phenotypic expression of the genetic defect is highly variable and appears to be more common in familial cases than in others (see Table 1).[11]

A 50% deficit in aminolevulinic acid dehydratase (ALAD) activity occurs in as many as 2% of the general population, although ALAD deficiency requires more than 90% inhibition of this enzyme. The low incidence of homozygous patients, given the relatively high prevalence of the heterozygous enzyme deficit, suggests that the homozygous deficit may result in death in utero.

Both the tissue and erythropoietic isoforms of porphobilinogen (PBG) deaminase are produced from the same gene by means of alternative splicing controlled by separate promoters. More than 100 mutations have been identified. Specific mutations are conserved within families, allowing for the screening of family members when a patient's genetic defect is known. Clinical disease is associated with a 50% or greater reduction in enzyme function. PBG deaminase has 3 mutation patterns:

  • Type I is a single-base error resulting in an amino acid substitutions or truncated proteins.

  • Type II (the Finish mutation) is localized to the tissue isoform of the enzyme.

  • Type III is a deletion in 1 of 2 exons that produces a structurally abnormal protein.

Coproporphyrinogen oxidase is located in the intermembrane space of the mitochondria and loosely associated with the outer face of the inner mitochondrial membrane. A single promoter site appears to be differentially regulated to produce the erythroid and nonerythroid isoforms. Significant genetic heterogeneity accounts for the abnormal function of coproporphyrinogen oxidase in HCP, making routine genetic screening impossible. Heterozygous and homozygous individuals have a 50% and 90-98% reduction in enzyme activity, respectively.

Protoporphyrinogen oxidase is located on the outer face of the inner mitochondrial membrane. A 50% reduction in activity consistently occurs across all tissue tested in affected individuals. The R59W defect may account for 95% of affected individuals in South Africa, whereas mutations in others are heterogeneous. Homozygous and doubly heterozygous individuals typically develop severe photomutilation with brachydactyly, nystagmus, seizures, and sensory neuropathy without acute episodes. Mental retardation is common in this neonatal form of variegate porphyria (VP).

 

DDx

 

Workup

Laboratory Studies

During acute episodes of porphyria, monitor electrolytes and serum osmolarity because hyponatremia and/or syndrome of inappropriate secretion of antidiuretic hormone can develop and cause seizures.

With the exception of aminolevulinic acid dehydratase (ALAD) deficiency, acute porphyrias can be diagnosed during acute episodes with 2 quick bedside tests to identify PBG. Both tests require porphobilinogen (PBG) levels 4 times the upper limit of normal. In either test, PBG reacts with para-dimethylaminobenzaldehyde (DMAB) to form a red compound. (Phenazopyridinium chloride, methyl red, and urosein may also turn the urine red under acidic conditions; these confounding factors can be excluded by testing a mixture of urine with hydrochloric acid. No simple tests are available to exclude compounds such as cascara sagrada, levomepromazine, methyldopa, antipyrine, phylloerythrinogen, indoles, and pyrrolic acids.)

Hoesch test is the simpler of the 2 tests and less prone to misinterpretation. For this test, mix 1-2 drops of urine with 1 mL of 6-mol/L hydrochloric acid (HCl) and 20 mg of DMAB. Immediate development of a cherry-red color at the top of the mixture indicates a positive result.

For the Watson-Schwartz test, mix 7.5 mL of a DMAB solution (10 mg/mL HCl) with 5 mL water. Mix 1 mL of the solution with 1 mL urine. Immediate formation of a red color suggests PBG excess. A positive result is confirmed by adding 2 mL saturated sodium acetate and then 3 mL chloroform to the positive mixture. After vigorous shaking, a red upper aqueous phase and a pink lower organic solution phase confirms a positive result.

Quantitative urine porphyrin levels vary. PBG levels vary approximately 20% when measured on a week-to-week basis and vary 25% when measured at a 10-week interval. This means that the probability that the 2-fold increase in PBG concentration is actually related to the patient's disease is 80%. Porphyrin levels are elevated during an episode; hereditary coproporphyria (HCP) and variegate porphyria (VP) have identical urine porphyrin profiles and can be differentiated by examining stool porphyrins.

Table 3. Quantitative Urine Porphyrin Levels (Open Table in a new window)

Level

ALAD Deficiency

Acute Intermittent Porphyria (AIP)

Congenital Erythropoietic Porphyria (CEP) and Porphyria Cutanea Tarda (PCT)

HCP and VP

ALA

Significantly increased

Significantly increased

Normal

Significantly increased

PBG

Increased

Significantly increased

Normal

Significantly increased

Uroporphyrin

Normal

Increased

Significantly increased

Increased

Coproporphyrin

Significantly increased

Increased

Increased

Significantly increased

 

Comparing the relative increase in PBG levels during acute attacks with the asymptomatic period may be a more sensitive marker for acute neuroporphyria when compared with absolute PBG values. Patients with AIP, VP, or HCP have 2.3-50.5–fold increases in PBG levels during acute attacks.

ALAD deficiency can be diagnosed by detecting numerous fluorescent erythrocytes by microscopically examining the blood with a 100-W iodine-tungsten lamp.

Quantitative stool studies help differentiate between HCP and VP because these disorders have identical urine porphyrin profiles.

Table 4. Quantitative Stool Porphyrin levels (Open Table in a new window)

Level

HCP

VP

Coproporphyrin

Significantly increased

Increased

Protoporphyrin

Increased

Significantly increased

 

Despite their limitations, functional assays can help in diagnosing porphyria. ALAD and PBG enzymes are measured in erythrocytes. In ALAD deficiency, a functional deficiency of 25% or greater is diagnostic. This deficit is also detected in lead poisoning and in hereditary tyrosinemia. PBG deaminase is deficient in many patients with AIP; however, in 10% of patients with AIP, the enzyme defect is limited to the liver or housekeeping enzyme. Other assays (eg, test for coproporphyrinogen oxidase in lymphocytes) are available but unreliable.

Many genetic defects responsible for porphyria have been identified. In general, a large number of defects account for each porphyria. This finding limits the use of genetic testing to only 2 situations:

  • If a genetic defect is known in an individual, his or her family members can be screened.

  • Certain ethnic groups have a high prevalence of a particular mutation. For example, Dutch and Swedish Laplanders have a specific mutation in AIP, and many South African families have a specific mutation in VP.

Imaging Studies

MRI may reveal selective disturbance on white matter tracts that become myelinated and develop postnatally.

Gray matter and white matter in the brainstem and cerebellum appear to be preserved.

Other Tests

Electromyography and nerve conduction studies are nonspecific.

In patients with porphyrias, motor nerve conduction velocities are usually normal.

Partial antidromic block with significantly slowed conductance may be seen during asymptomatic periods in patients with VP or AIP.

Changes consistent with reinnervation may occur during the recovery of muscle weakness.

Histologic Findings

Peripheral nervous system

Histology shows axonal degeneration and patchy demyelination of motor axons, particularly short motor axons, which innervate the proximal and bulbar muscles. Axons are thin and irregular, with vacuolization, degeneration, and cellular infiltration. Neuronal loss and chromatolysis of the anterior horn cells may be secondary to retrograde degeneration. Chromatolysis of cranial nerve nuclei, commonly the dorsal vagus nucleus and autonomic nervous system ganglia (eg, celiac ganglion), may be observed.

CNS

Histologic evaluation may show chromatolysis and vacuolization of neurons and selective involvement of oligodendrocytes. Other findings include focal perivascular demyelination, reactive gliosis, and localized changes in the supraoptic and paraventricular nuclei of the hypothalamus.

 

Treatment

Medical Care

Consider an appropriate period of first-line conservative therapy in patients with acute porphyria before administering heme for injection. The duration of conservative treatment depends on the patient's presenting condition and clinical course. Start a hematin infusion immediately if clinical deterioration is evident to prevent neuronal damage.

Conservative first-line therapy includes the following:

  • Remove potentially offending medications.

  • Administer intravenous (IV) fluid with a substantial carbohydrate supply (eg, dextrose 500 g/d).

  • Control pain with opiates.

  • Relieve nausea and vomiting with phenothiazines.

If conservative treatment proves unsatisfactory, administer an IV heme infusion for 3-14 days.

Hematin is the only heme compound currently approved for use in the United States. Heme arginate (Normosang) is a more stable heme compound and has a lower frequency of adverse effects. Although this compound has been used with success in Europe and South Africa, it has not been approved for use in the United States.[12]

Heme requires prompt administration for clinical benefit. Episodes of porphyria can cause irreversible neuronal damage. Heme therapy is intended to prevent an episode from reaching the critical stage of neuronal degeneration.

Fecal urobilinogen increases in proportion to the amount of hematin administered; this observation suggests an enterohepatic pathway as a route of elimination. Bilirubin metabolites are also excreted in the urine after hematin administration.

Urinary concentrations of porphyrins can be followed to monitor treatment efficacy. A decrease in aminolevulinic acid (ALA), uroporphyrinogen, porphobilinogen (PBG), and/or coproporphyrin values indicates successful treatment.

Strictly follow recommended dosing guidelines because asymptomatic reversible renal shutdown can occur when a greatly excessive dose of hematin is administered in a single infusion. However, recommended doses of hematin do not impair renal function.

Liver transplantation was effective in a case of severe acute intermittent porphyria (AIP). Studies of gene therapy in animal models to restore PBG activity are ongoing.

Several factors complicate the treatment of seizures in porphyria. The liver metabolizes most anticonvulsants are metabolized, at least to some extent, and most anticonvulsants induce the cytochrome P-450 enzyme system.

Acute seizure control includes the following:

  • Magnesium sulfate and diazepam are first-line drugs for acute seizure control.

  • Lorazepam is generally the first-line drug for status epilepticus and is safe to use in patients with porphyria.

  • Correct acute electrolyte abnormalities because seizures are commonly associated with such abnormalities.

Epilepsy control includes the following:

  • Gabapentin is not metabolized by the liver and is reportedly successful for long-term seizure control.

  • Diazepam per rectal is useful for outpatient control of prolonged seizures.

Correct electrolyte abnormalities. Hyponatremia can be corrected with an infusion of normal saline or half normal saline, depending on the level of volume depletion and hyponatremia. However, fluid restriction and diuretics may be needed if the patient exhibits signs of syndrome of inappropriate antidiuretic hormone secretion.

Autonomic outflow is managed by the administration of beta-blockers. Acute hypertension must be managed with appropriate emergency agents.

Psychiatric symptoms are typically controlled by administering phenothiazines (eg, chlorpromazine). These medications can also help relieve nausea.

Givosiran (Givlaari) was approved by the US Food and Drug Administration (FDA) for adults with acute hepatic porphyrias (AHP), in which attacks are caused by induction of the enzyme 5-aminolevulinic acid synthase 1 (ALAS1). Givosiran is a small interfering RNA agent. Via RNA interference, it leads to degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes, which in turn lowers elevated liver ALAS1 mRNA levels.

Approval of givosiran was based on the ENVISION phase 3 trial (n=94). In patients with acute intermittent porphyria, givorsan was associated, relative to placebo, with a 74% mean reduction in the annualized composite rate of porphyria attacks.[13]

Consultations

An expert in porphyria should assist in the diagnosis and treatment of patients with acute and chronic cases, as the management of porphyria involves many disciplines. Such experts may be certified in metabolic diseases, gastroenterology, or hematology.

Consultation with a neurologist may be needed if seizures or neuropathy develop.

Consultation with a physical therapist may be needed if muscle weakness develops.

Consultation with a psychiatrist may be necessary for the management of short-term and/or long-term psychiatric issues.

Consultation with a specialist in reproductive medicine may be necessary for menses and birth control.

Consultation with a cardiologist may be needed if hypertension develops.

Consultation with an anesthesiologist is necessary before a patient is sedated for a minor procedure or surgery.[14]

Seek a consultation with an ophthalmologist if ocular manifestations arise.

Diet

A high-carbohydrate diet can mitigate the disease. A low-carbohydrate diet is strictly forbidden.

The patient should maintain adequate fluid intake to ensure good clearance of porphyrins.

A low-salt, low-fat, and low-cholesterol diet may be prudent if hypertension develops.

Activity

Instruct patients to avoid activities that put them at risk for dehydration, exhaustion, or carbohydrate depletion.

 

Medication

Medication Summary

Conservative therapy includes IV fluid with a substantial carbohydrate supply (eg, dextrose 500 g/d), pain control with opiates, and relief of nausea and vomiting with phenothiazines. If conservative treatment proves unsatisfactory, an IV heme infusion is indicated. Seizure control using anticonvulsants is also indicated.

Heme analogues

Class Summary

Iron-containing metalloporphyrins reduce hepatic and marrow synthesis of porphyrin by inhibiting aminolevulinic acid (ALA) synthetase, the rate-limiting enzyme in the porphyrin biosynthetic pathway. Clinical symptoms (eg, pain, hypertension, tachycardia, mental status changes, neuropathy) may be controlled.

Heme arginate (Normosang; Leiras Medica, Finland) is not approved for use in the United States. Heme arginate may have a lower frequency of thrombophlebitis than hemin (Panhematin) and improves drug metabolism mediated by the cytochrome P-450 system.

Hemin (Panhematin)

Heme analogue for treatment of acute episodes. Enzyme inhibitor derived from processed RBCs and iron-containing metalloporphyrin. Was known as hematin, term used to describe chemical reaction product of hemin and sodium carbonate solution.

Anticonvulsants

Class Summary

Seizures, which can occur as a neurologic manifestation of acute porphyria, are best treated with a drug not metabolized by the liver.

Gabapentin (Neurontin)

Structurally related to GABA but does not interact with GABA receptors; not metabolically converted into GABA or a GABA agonist; does not inhibit GABA uptake or degradation. Among safest anticonvulsants, no significant interactions, and not metabolized by the liver. Usually used as adjunct anticonvulsant but can be first-line medication for long-term seizure control in some circumstances.

Magnesium sulfate

Depresses CNS, possibly by inhibiting acetylcholine release by motor nerve impulses. Blocks peripheral neuromuscular transmission. Used for acute seizure control. Elemental magnesium 49.3 mg (4.1 mEq) = 500 mg magnesium sulfate

Diazepam (Valium, Diastat)

Long-acting PO, parenteral, and PR benzodiazepine, with antianxiety properties useful for acute seizure control. PR diazepam particularly useful for outpatients in whom seizures may occur.

Lorazepam (Ativan)

A benzodiazepine with antianxiety properties used for acute seizure control. Minimal respiratory and circulation adverse effects. Primarily eliminated by kidneys and metabolized by liver but not cytochrome pathway.

Analgesic agents

Class Summary

Opiates are first-line agents for pain control in porphyria because the pain is usually intense and because these medications are safe to use for this condition.

Morphine (Generic, Astramorph PF, Duramorph)

DOC for analgesia. Can be administered IV or IM. Wide spectrum of pharmacologic effects, including analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished GI motility, and physical dependence. Continuous infusion useful for extended use and minimizes tolerance. Hepatic glucuronidation to morphine-3-glucuronide pharmacologically inactivates morphine; major excretion pathway of conjugate is through kidneys. Half-life 1.5-4.5 h.

Meperidine (Demerol)

Analgesic with multiple actions similar to those of morphine; may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine. Do not exceed administration >48 h because of risk of seizures secondary to accumulation of normeperidine metabolite.

Antipsychotics/antiemetics

Class Summary

Phenothiazines have antiemetic and antipsychotic properties, making them the medication of choice for acute porphyria episodes.

Chlorpromazine (Thorazine, Ormazine)

Principally psychotropic but also exerts sedative and antiemetic activity. Acts at all levels of CNS but primarily subcortical levels. Strong antiadrenergic and weak anticholinergic, antihistaminic, and antiserotonergic activity.

Beta-adrenergic blocking agents

Class Summary

These agents reduce sympathetic hyperactivity during acute episodes.

Propranolol (Inderal)

Competitive beta-adrenergic antagonist that blocks chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation. Reduces increased sympathetic outflow due to acute neuropathy associated with porphyria, but insufficient to treat hypertensive emergencies associated with acute porphyria episodes.

Hormones

Class Summary

Premenstrual episodes occur in some women. Inhibiting or controlling the menstrual cycle can control these episodes.

Leuprolide (Lupron)

Gonadotropin-releasing hormone agonist; potent inhibitor of gonadotropin secretion when given continuously. Long-term stimulation causes downregulation of gonadotropins and suppression of ovarian and testicular steroidogenesis, essentially inducing menopause. Effects reversible on discontinuation. Use under guidance of specialist in reproductive medicine.

RNAi Agents

Class Summary

Small interfering RNA agents. Via RNA interference, they lead to degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes, which in turn lowers elevated liver ALAS1 mRNA levels. This decreases circulating levels of the neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), both of which are linked to attacks and other manifestations of the acute hepatic porphyrias (AHP).

Givosiran (Givlaari)

Indicated for adults with acute hepatic porphyria.

 

Follow-up

Further Outpatient Care

Regularly monitor blood pressure in patients with acute porphyria.

Monitor renal and liver function.

Folic acid may clinically and biochemically benefit patients with acute intermittent porphyria (AIP).

Physical therapy may be required if significant motor neuropathy persists after the patient's discharge from the hospital.

Central pain syndromes (resulting from sensory neuropathies) can be treated with gabapentin.

Inpatient & Outpatient Medications

Many medications can induce or worsen porphyria (see Deterrence/Prevention), whereas others have not been associated with worsening porphyria. Many medications have not been tested in patients with known porphyria.

The list of probably safe medications below is not exhaustive; any medication prescribed to a patient with porphyria should be researched.

Drugs not associated with worsening porphyria include the following:

  • Acetaminophen

  • Adrenaline

  • Amitriptyline

  • Aspirin

  • Atropine

  • Bromides

  • Chloral hydrate

  • Chlordiazepoxide

  • Colchicine

  • Diazepam

  • Digoxin

  • Diphenhydramine

  • Ethylenediaminetetraacetic acid (EDTA)

  • Ether

  • Glucocorticoids

  • Guanethidine

  • Ibuprofen

  • Imipramine

  • Indomethacin

  • Insulin

  • Labetalol

  • Lithium

  • Methylphenidate

  • Naproxen

  • Narcotics

  • Neostigmine

  • Nitrous oxide

  • Penicillamine

  • Penicillin

  • Phenothiazines

  • Procaine

  • Propranolol

  • Succinylcholine

  • Tetracycline

  • Thyroxine

  • Tubocurarine

A more extensive list of drugs that are probably safe is available at the University of Queensland Porphyria Research Unit Web site.

Alcohol ingestion can precipitate acute episodes.

Cigarette smoking can increase the risk of acute episode.

Fasting and low-carbohydrate diets are forbidden.

Controlling menses can treat premenstrual exacerbation of porphyria.

Although hormone analogs of luteinizing hormone releasing hormone can suppress menses, these medications essentially induce menopause, which has its own deleterious effects. Therefore, oral contraceptives (eg, a low-dose estrogen-progesterone combination pill) may be useful, if tolerated.

Standard oral contraceptive pills may elicit porphyria symptoms (in 15% of patients) or episodes (in 5% of patients). However, in several cases, further episodes were prevented with the administration of oral contraceptive pills (especially low-dose estrogen or an estrogen-progesterone combination) immediately after a menses-elicited acute episode resolved.

Use of a testosterone implant is reported in 1 case.

Deterrence/Prevention

Many medications induce or worsen acute and cutaneous porphyria, and many of these are metabolized by the liver, at least to some extent. Liver metabolism may induce the cytochrome P-450 enzymes that require heme, inducing heme production.

Any medication used in a patient with porphyria should be investigated. Many medications have not been used for patients with porphyria; therefore, their potential for worsening porphyria is not known.

The list of common medications below may help to determine whether a medication could have triggered a porphyria reaction in a patient without a diagnosed disorder. Note that the effect of many medications on porphyria is highly idiosyncratic. For example, some patients may tolerate these medications well, and some of these medicines can be used to treat patients with porphyria.

Drugs potentially unsafe in porphyria include the following:

  • Alfaxalone

  • Alkylating agents

  • Antipyrine

  • Arthrotec

  • Barbiturates

  • Busulfan

  • Butalbital

  • Carbamazepine

  • Carisoprodol

  • Chlordiazepoxide

  • Chloroquine

  • Clonidine

  • Danazol

  • Danocrine

  • Dapsone

  • Diclofenac

  • Ergot

  • Erythromycin

  • Erythropoietin

  • Estrogens

  • Ethchlorvynol

  • Fluroxene

  • Griseofulvin

  • Heavy metals

  • Hydralazine

  • Ketamine

  • Mafenide

  • Meprobamate

  • Methoxsalen

  • Methyldopa

  • Metoclopramide

  • Nitrazepam

  • Nortriptyline

  • Pargyline

  • Pentazocine

  • Phenazopyridine

  • Phenobarbital

  • Phenoxybenzamine

  • Phenylbutazone

  • Phenytoin

  • Plaquenil

  • Porfimer

  • Primidone

  • Progestins

  • Pyrazinamide

  • Ranitidine

  • Rifampin

  • Spironolactone

  • Succinimides

  • Sulfonamides

  • Sulfonylureas

  • Theophylline

  • Tolazamide

  • Tranylcypromine

  • Valproate

A more extensive list of unsafe drugs is available at the University of Queensland Porphyria Research Unit Web site.

Alcohol ingestion can precipitate acute episodes.

Cigarette smoking can increase the risk of acute episode.

Fasting and low-carbohydrate diets are forbidden.

Controlling menses can treat premenstrual exacerbation of porphyria.

Although hormone analogs of luteinizing hormone releasing hormone can suppress menses, these medications essentially induce menopause, which has its own deleterious effects. Therefore, oral contraceptives (eg, a low-dose estrogen-progesterone combination pill) may be useful, if tolerated.

Standard oral contraceptive pills may elicit porphyria symptoms (in 15% of patients) or episodes (in 5% of patients). However, in several cases, further episodes were prevented with the administration of oral contraceptive pills (especially low-dose estrogen or an estrogen-progesterone combination) immediately after a menses-elicited acute episode resolved.

Use of a testosterone implant is reported in 1 case.

Complications

Hypertension and chronic renal insufficiency may occur.

Recurrent acute episodes increase the risk of neuropsychiatric symptoms during the symptomless phase of the disease.

For more than 90% of women, pregnancy does not exacerbate symptoms of porphyria or lead to acute episodes. However, approximately 8% of women may have symptoms of porphyria during pregnancy, and approximately 4% have acute episodes after delivery.

Prognosis

Patients with a history of episodes have an increased risk of future episodes. Persons with histories of multiple acute episodes also have an increased risk of future episodes.

Although urinary excretion of porphobilinogen (PBG) during the symptomless phase is positively correlated with the number of acute episodes, high variability limits its predictive accuracy. However, low PBG urinary excretion during the symptomless phase appears to indicate a low frequency of subsequent acute episodes.

Before 1980, acute episodes were a major cause of death. Improved management of porphyria has since reduced mortality rates during acute exacerbations.

Mortality appears to be associated with increased incidences of cardiovascular disease and hypertension, chronic renal failure, and hepatocellular carcinoma.

Patient Education

The following resources are useful for patient reference and education:

  • American Porphyria Foundation

  • Canadian Porphyria Foundation

  • National Institute of Diabetes & Digestive & Kidney Diseases

  • National Organization for Rare Disorders

  • Online Mendelian Inheritance in Man