Acute Porphyrias

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

• Vomiting

Abdominal 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.

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 strongly 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, delirium, depression, agitation, frank psychosis, hallucinations). Seizures, psychotic behavior, and hallucinations may be due to or exacerbated by hyponatremia or hypomagnesemia. Hyponatremia may occur during an acute attack due to excessive vasopressin1).

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, paresthesias, 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 (2). 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 (3).

1. 1. Jaramillo-Calle DA, Solano JM, Rabinstein AA, Bonkovsky HL: Porphyria-induced posterior reversible encephalopathy syndrome and central nervous system dysfunction. Mol Genet Metab 128(3):242–253, 2019. doi:10.1016/j.ymgme.2019.10.011

2. 2. Simon A, Pompilus F, Querbes W, et al: Patient perspective on acute intermittent porphyria with frequent attacks: A disease with intermittent and chronic manifestations. Patient 11(5):527–537, 2018. doi:10.1007/s40271-018-0319-3

3. 3. Saberi B, Naik H, Overbey JR, et al: Hepatocellular carcinoma in acute hepatic porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium. Hepatology 73(5):1736–1746, 2021. doi:10.1002/hep.31460

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 psychiatric 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 psychiatric 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 acid 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 enzyme ALAD in the red blood cells is readily measurable and can be helpful for establishing the diagnosis in ALAD-deficiency porphyria, in which ALAD activity is severely decreased (< 10% of normal). Similarly, PBG deaminase activity in red blood cells can be measured to help diagnose acute intermittent porphyria, which is suggested by red blood cell PBG deaminase levels that are approximately 50% of normal. However, in approximately 5% of patients with acute intermittent porphyria, PBG deaminase activity in red blood cells is normal. Thus, in many centers, genetic testing is replacing measurements of enzyme activity in red blood cells.

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 special testing 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, fecal porphyrins are not present in the quiescent phase of acute porphyria.

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. Specifically, there is a unique peak fluorescence at 626 nm in variegate porphyria, which is useful for establishing the correct diagnosis. This simple and useful test is not available in many large reference laboratories.

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 strongly preferred first in the index case and then repeated with targeted genetic testing in all first-degree relatives. In the rare instances when genetic testing has failed to unveil a pathogenic mutation, pertinent red blood cell enzyme activities may be measured. However, genetic testing is preferred for making a definitive diagnosis because of overlap of activities of RBC PBG deaminase, as already described, and because measurements of activities of coproporphyrinogen oxidase (CPOX) or protoporphyrinogen oxidase (PPOX) in white blood cells are difficult and no longer available, either at commercial or research laboratories.

• 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.

• 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.

1). There is no standardized regimen; a specialist should be consulted (1, 2).

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 (3, 4).

1. 1. Yarra P, Faust D, Bennett M, et al: Benefits of prophylactic heme therapy in severe acute intermittent porphyria. Mol Genet Metab Rep 19:100450, 2019. doi:10.1016/j.ymgmr.2019.01.002

2. 2. Kuo HC, Lin CN, Tang YF: Prophylactic heme arginate infusion for acute intermittent porphyria. Front Pharmacol 12:712305, 2021. doi:10.3389/fphar.2021.712305

3. 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(6): 549–558, 2019.

4. 4. Wang B, Rudnick S, Cengia, Bonkovsy HL: Acute hepatic porphyrias: Review and recent progress. Hepatol Commun 3:193−206, 2019.