(See also Overview of Porphyrias.)
Acute porphyrias include, in order of decreasing prevalence:
Patients with variegate porphyria and hereditary coproporphyria, with or without neurovisceral symptoms, may develop bullous eruptions especially on the hands, forearms, face, neck, or other areas of the skin exposed to sunlight.
Among heterozygotes, acute porphyrias are rarely expressed clinically before puberty; after puberty, they are expressed in only about 2 to 4%. Among homozygotes and compound heterozygotes, onset typically is in childhood, and symptoms are often severe.
Many precipitating factors exist, typically accelerating heme biosynthesis above the catalytic capacity of the defective enzyme. Accumulation of the porphyrin precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA), or in the case of ALAD-deficiency porphyria, ALA alone, results.
Attacks probably result from several, sometimes unidentifiable, factors. Identified precipitating factors include
Hormonal factors are important. Women are more prone to attacks than men, particularly during periods of hormonal change (eg, luteal phase of the menstrual cycle, during oral contraceptive use, during early weeks of gestation, in the immediate postpartum period). Nevertheless, pregnancy is not contraindicated.
Other factors include drugs, particularly those that induce hepatic ALA synthase and cytochrome P-450 enzymes. Attacks usually occur within 24 hours after exposure to a precipitating drug. A wide range of drugs are problematic, particularly barbiturates, hydantoins, other antiseizure drugs, sulfonamide antibiotics, and reproductive hormones ( progesterone and related steroids). However, the degree of risk and the level of certainty vary considerably; current information should be sought from online databases such as www.drugs-porphyria.org and the American Porphyria Foundation.
Exposure to sunlight precipitates cutaneous symptoms in variegate porphyria and hereditary coproporphyria.
Symptoms and signs of acute porphyrias involve the nervous system, abdomen, or both (neurovisceral). Attacks develop over hours or days and can last up to several weeks. Most gene carriers experience no, or only a few, attacks during their lifetime. Others experience recurrent symptoms. In women, recurrent attacks often coincide with the luteal phase of the menstrual cycle.
The symptoms and signs of attacks are nonspecific and can mimic many other disease processes. Constipation, fatigue, mental status changes (often described as "fogginess"), and insomnia typically precede an acute attack. The most common symptoms of an attack are abdominal pain and vomiting. The pain may be excruciating and is disproportionate to abdominal tenderness or other physical signs. Abdominal manifestations may result from effects on visceral nerves. Usually, there is no inflammation, the abdomen is not tender, and there are no peritoneal signs. However, a minority of patients with acute hepatic porphyrias also develop acute pancreatitis, for which alternative potential causes, such as gallstones, excess alcohol use, and severe hypertriglyceridemia, are not found. Temperature and white blood cell count are usually normal or only slightly increased. Bowel distention may develop as a result of paralytic ileus. The urine is red or reddish brown and positive for porphobilinogen during an attack.
All components of the peripheral nervous system and the central nervous system may be involved. Motor neuropathy is common with severe and prolonged attacks. Muscle weakness usually begins in the extremities but can involve any motor neuron or cranial nerve and proceed to tetraplegia. Bulbar involvement can cause respiratory failure.
Central nervous system involvement may cause seizures or mental disturbances (eg, apathy, depression, agitation, frank psychosis, hallucinations). Seizures, psychotic behavior, and hallucinations may be due to or exacerbated by hyponatremia or hypomagnesemia, which can also contribute to cardiac arrhythmias. Hyponatremia may occur during an acute attack due to excessive vasopressin (antidiuretic hormone [ADH]) release and/or administration of hypotonic IV solutions (5% or 10% dextrose in water), a standard therapy for acute attacks. Some patients develop features of the posterior reversible encephalopathy syndrome (PRES), characterized by headache, altered mental status, seizures, and visual loss thought to be due to edema in the posterior occipital and parietal lobes.
Excess catecholamines generally cause restlessness and tachycardia. Rarely, catecholamine-induced arrhythmias cause sudden death. Labile hypertension with transiently high blood pressure may cause vascular changes progressing to irreversible hypertension if untreated. Chronic kidney disease in acute porphyria is multifactorial; acute hypertension (possibly leading to chronic hypertension) is likely a main precipitating factor. However, genetic factors, especially a genetic variation in the peptide transporter 2 (PEPT2) gene, which encodes a peptide and amino acid transporter that can affect reabsorption of ALA in the proximal tubule, have been found in patients with acute intermittent porphyria who have developed chronic kidney disease. Specifically, carriers of the higher affinity variant (PEPT2*1*1) have been found to have more severe renal dysfunction than carriers of the lower affinity variants.
Some patients have prolonged symptoms of lesser intensity (eg, obstipation, fatigue, headache, back or thigh pain, paresthesia, tachycardia, dyspnea, insomnia, depression, anxiety or other disturbances of mood, seizures). Chronic symptoms between attacks probably occur in many patients, especially those who have experienced more than one acute attack, with pain the most frequent symptom. Many patients experience daily symptoms.
Fragile skin and bullous eruptions may develop on sun-exposed areas, even in the absence of neurovisceral symptoms. Often patients are not aware of the connection to sun exposure. Cutaneous manifestations are identical to those of porphyria cutanea tarda; lesions typically occur on the dorsal aspects of the hands and forearms, the face, ears, and neck.
Motor involvement during acute attacks may lead to persistent muscle weakness and muscle atrophy between attacks. Cirrhosis, hepatocellular carcinoma, systemic arterial hypertension, and renal impairment become more common after middle age in acute intermittent porphyria and possibly also in variegate porphyria and hereditary coproporphyria, especially in patients with previous porphyric attacks.
Misdiagnosis is common because the acute attack is confused with other causes of acute abdomen (sometimes leading to unnecessary surgery) or with a primary neurologic or mental disorder. However, in patients previously diagnosed as gene carriers or who have a positive family history, porphyria should be suspected. Still, even in known gene carriers, other causes must be considered.
Red or reddish brown urine, not present before onset of symptoms, is a cardinal sign and is often present during full-blown attacks. A urine specimen should be examined in patients with abdominal pain of unknown cause, especially if severe constipation, vomiting, tachycardia, muscle weakness, bulbar involvement, or mental symptoms occur.
If porphyria is suspected, the urine is analyzed for PBG using a rapid qualitative or semiquantitative determination. A positive result or high clinical suspicion necessitates quantitative urinary ALA, PBG, and creatinine measurements, preferentially obtained from the same specimen. PBG and ALA levels, normalized to urinary creatinine concentration, > 5 times normal indicate an acute porphyric attack unless patients are gene carriers in whom porphyrin precursor excretion occurs at similar levels even during the latent phase of the disorder.
If urinary PBG/creatinine and ALA/creatinine ratios are normal, an alternative diagnosis must be considered. Measurement of urinary total porphyrins and high-performance liquid chromatography profiles of these porphyrins are helpful. Elevated urinary ALA and coproporphyrin with normal or slightly increased PBG suggests lead poisoning, delta-aminolevulinic dehydratase (ALAD)-deficiency porphyria, or hereditary tyrosinemia type 1. Analysis of a 24-hour urine specimen is not necessary. Instead, a random urine specimen is used, and PBG and ALA levels are corrected for dilution by relating to the creatinine level of the sample.
Electrolytes, including magnesium, should be measured. Hyponatremia may be present because of excessive vomiting or diarrhea after hypotonic fluid replacement or because of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Because treatment does not depend on the type of acute porphyria, identification of the specific type is valuable mainly for finding gene carriers among relatives. When the type and mutation are already known from previous testing of relatives, the diagnosis is clear but may be confirmed by gene analysis.
Activity of the enzymes ALAD and PBG deaminase in the red blood cells is readily measurable and can be helpful for establishing the diagnosis in ALAD-deficiency porphyria and acute intermittent porphyria, respectively. In delta aminolevulinic dehydratase (ALAD)-deficiency porphyria, activity of ALAD in red blood cells is severely decreased (< 10% of normal). Red blood cell PBG deaminase levels that are about 50% of normal suggest acute intermittent porphyria.
If there is no family history to guide the diagnosis, the different forms of acute porphyria are distinguished by characteristic patterns of porphyrin (and precursor) accumulation and excretion in plasma, urine, and stool. When urinalysis reveals increased levels of ALA and PBG, fecal porphyrins may be measured. Fecal porphyrins are usually normal or minimally increased in acute intermittent porphyria but elevated in hereditary coproporphyria and variegate porphyria. Often, these markers are not present in the quiescent phase of the disorder. Plasma fluorescence emission after excitation with Soret band of light (~410 nm) can be used to differentiate hereditary coproporphyria and variegate porphyria, which have different peak emissions.
Children of a gene carrier for an autosomal dominant form of acute porphyria (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have a 50% risk of inheriting the disorder. In contrast, children of patients with ALAD-deficiency porphyria (autosomal recessive inheritance) are obligate carriers but are very unlikely to develop clinical disease. Because early diagnosis followed by counseling reduces the risk of morbidity, children in affected families should be tested before the onset of puberty. Genetic testing is used if the mutation has been identified in the index case. If not, pertinent red blood cell or white blood cell enzyme levels are measured. However, genetic testing is preferred for making a definitive diagnosis because measurement of enzyme activity in red blood cells is subject to variations in how samples are processed and shipped, there is overlap between activity of PBG deaminase in people without porphyria and patents with AIP, and about 5% of patients with AIP have normal PBG deaminase activity in red blood cells. Gene analysis can be used for in utero diagnosis (using amniocentesis or chorionic villus sampling) but is seldom indicated because of the favorable outlook for most gene carriers.
Advances in medical care and self-care have improved the prognosis of acute porphyrias for symptomatic patients. Still, some patients develop recurrent crises or progressive disease with permanent paralysis or renal failure. Also, frequent need for opioids analgesics may give rise to opioid dependence.
Treatment of the acute attack is identical for all the acute porphyrias. Possible triggers (eg, excessive alcohol use, drugs) are identified and eliminated. Unless the attack is mild, patients are hospitalized in a darkened, quiet, private room. Heart rate, blood pressure, and fluid and electrolyte balance are monitored. Neurologic status, bladder function, muscle and tendon reflex function, respiratory function, and oxygen saturation are continuously monitored. Symptoms (eg, pain, vomiting) are treated with nonporphyrinogenic drugs as needed.
Dextrose 300 to 500 g daily down-regulates hepatic ALA synthase (ALAS 1) and relieves symptoms. Dextrose can be given by mouth if patients are not vomiting; otherwise, it is given IV. The usual regimen is 3 L of 10% dextrose solution, given by a central venous catheter over 24 hours (125 mL/hour). However, to avoid overhydration with consequent hyponatremia, 1 L of 50% dextrose solution can be used instead.
IV heme is more effective than dextrose and should be given immediately in severe attacks, electrolyte imbalance, or muscle weakness. Heme usually resolves symptoms in 3 to 4 days. If heme therapy is delayed, nerve damage is more severe and recovery is slower and possibly incomplete. Heme is available in the US as lyophilized hematin to be reconstituted in a glass vial with sterile water. The dose is 3 to 4 mg/kg IV once a day for 4 days. An alternative is heme arginate, which is given at the same dose, except that it is diluted in 5% dextrose or half-normal or quarter-normal saline. Hematin and heme arginate may cause venous thrombosis and/or thrombophlebitis. Risk of these adverse events appears to be lower if the heme is administered bound to human serum albumin. Such binding also decreases the rate of development of hematin aggregates. Thus, most authorities recommend administration of hematin or heme arginate with human serum albumin (1).
Anecdotal experience indicates that tolvaptan, a vasopressin receptor blocker, is helpful in the management of hyponatremia during acute attacks.
Givosiran has recently become available for treatment of adults with acute hepatic porphyria. It is a small interfering RNA (siRNA) that selectively targets and markedly down-regulates hepatic ALA synthase-1 (2, 3). When given at a dose of 2.5 mg/kg subcutaneously once a month, it reduces the frequency and severity of recurrent attacks of AIP. Givosiran is taken up by hepatocytes where it decreases activity of ALA synthase-1, leading to marked decreases in plasma and urinary concentrations of ALA and PBG, fewer acute attacks, less need for "rescue" IV heme, and improved quality of life. Givosiran has generally been well-tolerated, with only a few patients experiencing elevations in serum alanine aminotransferase and aspartate aminotransferase (without jaundice) severe enough to require temporary or permanent cessation of the drug. It also has been associated with mild increases in serum creatinine levels.
In patients with severe recurrent attacks, who are at risk of renal damage or permanent neurologic damage, liver transplantation is an option. Successful liver transplantation leads to permanent cure of acute intermittent porphyria. The deficiency in hepatic PBG deaminase is corrected with liver transplantation, resulting in biochemical (normal levels of PBG and ALA) and symptomatic resolution (4). Clinical experience with liver transplantation for AIP has been limited to 14 described cases, with survival rates similar to transplantation for other indications; survival at 3 months was 93%, and at 5 years, survival was 77%. Liver transplantation has not been described in hereditary coproporphyria. One child with ALAD-deficiency porphyria underwent liver transplantation with a decrease in hospitalizations but no improvement in biochemical markers (5).
Although not recognized in the latest American Association for the Study of Liver Disease (AASLD) Practice Guideline as a distinct indication for liver transplantation, the hepatic porphyrias would accurately be included within the liver-based metabolic conditions with systemic manifestations. In the absence of standardized Model for End-Stage Liver Disease (MELD) exception points, liver transplantation for AIP would rely upon petition to the regional review board within the transplant center's United Network for Organ Sharing (UNOS) region.
Patients with acute porphyrias should not serve as liver donors even though their liver may appear structurally normal (ie, no cirrhosis) because recipients without previously diagnosed porphyria have developed acute porphyric syndromes; such an outcome helped establish that the acute porphyrias are hepatic disorders. Kidney transplantation, with or without simultaneous liver exchange, should be considered in patients with active disease and terminal renal failure because there is considerable risk that nerve damage will progress at the start of dialysis.
1. Bonkovsky HL, Healey JF, Lourie AN, and Gerron GG: Intravenous heme-albumin in acute intermittent porphyria. Evidence for repletion of hepatic hemoproteins and regulatory heme pools. Am J Gastroenterol 86: 1050–1056, 1991.
2. Balwani M, Sardh E, Ventura P, et al: Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. New Engl J Med 382: 2289–2301, 2020.
3. Sardh E, Harper P, Balwani M, et al: Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med 380: 549–558, 2019.
4. Dowman JK, Gunson BK, Mirza DF, et al: Liver transplant for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis. Liver Transpl 18: 195–200, 2012. doi: 10.1002/lt.22345
5. Thunell S, Henrichson A, Floderus Y, et al: Liver transplantation in a boy with acute porphyria due to aminolaevulinate dehydratase deficiency. Eur J Clin Chem Clin Biochem 30: 599–606, 1992.
Carriers of acute porphyria should avoid the following:
Diets for obesity should provide gradual weight loss and be adopted only during periods of remission. Carriers of variegate porphyria or hereditary coproporphyria should minimize sun exposure; sunscreens that block only ultraviolet B light are ineffective, but opaque zinc oxide or titanium dioxide preparations are beneficial. Support associations, such as the American Porphyria Foundation and the European Porphyria Network, can provide written information and direct counseling.
Patients should be identified prominently in the medical record as carriers and should carry a card or wear medical alert jewelry verifying the carrier state and precautions to be observed.
A high-carbohydrate diet may decrease the risk of acute attacks. Some patients can sometimes treat mild acute attacks by increasing their intake of dextrose or glucose. Prolonged use should be avoided in order to decrease risk of obesity and dental caries.
To prevent renal damage, chronic hypertension should be treated aggressively (using safe drugs). Patients with evidence of impaired renal function are referred to a nephrologist.
The incidence of hepatocellular cancer is high among carriers of acute porphyria, especially in patients with active disease. Patients who are > 50 should undergo yearly or twice yearly surveillance, including liver screening with ultrasonography. Early intervention can be curative and increases life expectancy.
Patients who experience recurrent and predictable attacks (typically women with attacks related to the menstrual cycle) can be given monthly givosiran at a dose of 2.5 mg/kg body weight by subcutaneous injection. Alternatively, patients may benefit from prophylactic heme therapy given shortly before the expected onset of an acute attack or weekly as prophylaxis, which is less expensive (1). There is no standardized regimen; a specialist should be consulted.
Frequent premenstrual attacks in some women are aborted by administration of a gonadotropin-releasing hormone agonist plus low-dose estrogen. Low-dose oral contraceptives are sometimes used successfully, but the progestin component is likely to exacerbate the porphyria.
The introduction of wild-type messenger RNA (mRNA) for porphyrinogen deaminase H into hepatocytes to increase levels of the enzyme is another approach that has demonstrated promise in pre-clinical studies (2, 3).
1.Yarra P, Faust D, Bennett, M, et al: Benefits of prophylactic heme therapy in severe acute intermittent porphyria. Mol Genet Metab Rep 19: , 2019, Epub. Doi: 10/1016/j/ymgmr.2019.01.002
2. Sardh E, Harper P, Balwani M, et al: Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med 380(6): 549–558, 2019.
3. Wang B, Rudnick S, Cengia, Bonkovsy HL: Acute hepatic porphyrias: Review and recent progress. Hepatology Communications 3:193−206, 2019.
Acute porphyrias cause intermittent attacks of abdominal pain and neurologic symptoms; some types also have cutaneous manifestations that are triggered by sun exposure.
Attacks have many triggers, including hormones, drugs, low-calorie and low-carbohydrate diets, and alcohol ingestion.
Attacks typically involve severe abdominal pain (with a non-tender abdomen) and vomiting; any component of the peripheral and central nervous system may be affected but muscle weakness is common.
Urine is often reddish-brown during an attack.
Do a qualitative urine test for porphobilinogen (PBG) and confirm a positive result with quantitative delta-aminolevulinic acid (ALA) and PBG measurements.
Treat acute attacks with oral or IV dextrose and, for severe attacks, IV heme.
Treat patients with recurrent acute attacks with IV heme, givosiran, or, in some cases, liver transplantation.
The following are some English-language resources that may be useful. Please note that The Manual is not responsible for the content of these resources.
Martin P, DiMartini A, Feng S, et al: Evaluation for Liver Transplantation in Adults: 2013 Practice Guideline by the AASLD and the American Society of Transplantation. American Association for the Study of Liver Diseases 2013.
American Porphyria Foundation: Aims to educate and support patients and families affected by porphyrias and to support research into treatment and prevention of porphyrias
American Porphyria Foundation: Safe/Unsafe Database: Provides an up-to-date list of drugs available in the United States to assist physicians in prescribing for patients with porphyrias
European Porphyria Network: Promotes clinical research about porphyrias
The Drug Database for Acute Porphyrias: Provides an up-to-date list of drugs available in Europe to assist physicians in prescribing for patients with porphyrias
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