There are 4 acute hepatic porphyrias (AHPs), including 3 with dominant inheritance: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). The fourth AHP is a rare autosomal recessive disorder, 5ALA-dehydratase deficiency porphyria (ADP). The more common AIP, VP, and HCP have low penetrance and present with neurovisceral attacks, primarily in women during their child-bearing years. The rare ADP has close to full penetrance and presents in infancy or early childhood with impaired neurodevelopment and occasional neurovisceral attacks. Porphyric neuropathy (PN) has variable expression and severity and may progress to quadriparesis and respiratory weakness if diagnosis and treatment are delayed. Early diagnosis of AHP and avoidance or elimination of potential precipitants can prevent neurologic complications. Broader understanding of AHP pathogenesis has led to development of new therapies, which we summarize in this review.

Pathogenesis

The AHPs are inherited metabolic disorders caused by specific enzyme deficiencies in the heme biosynthesis pathway that result in heme precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulation in the liver. Heme production in the liver is tightly controlled by the rate-limiting enzyme ALA synthase-1 (ALAS1), the first enzyme of the 8-step heme synthesis pathway (Figure). Common precipitants of acute neurovisceral attacks (eg, alcohol, smoking, calorie deprivation, certain hormones, and porphyrinogenic drugs) induce ALAS1 messenger RNA (mRNA) expression and increase neurotoxic heme precursor production (ie, increase ALA and PBG). Heme deficiency and direct ALA neurotoxicity are thought to be mechanisms for neurologic effects of AHPs.1

<p>Figure. The Heme Biosynthetic Pathway and Porphyria Treatment. In the mitochondria, glycine and succinyl-CoA are converted to δ-aminolevulinic acid (ALA) by δ-aminolevulinic acid synthase (ALAS1), the rate-limiting enzyme in the pathway; all enzymes are blue. In the cytoplasm, ALA is metabolized to porphobilinogen (PBG) and then to heme; when an enzyme in this pathway is deficient, ALA and PBG accumulate and have neurovisceral effects causing porphyrias (red), including acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and 5-ALA-dehydratase (ALAD)-deficiency porphyria (ADP). Currently used treatments (dark green) decrease ALAS1 activity by inhibiting production (givosiran) or suppressing induction (heme, glucose) of ALAS-1. Investigational treatments (light green) are being developed to replace PBG deaminase (PBGD) activity.</p>

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Figure. The Heme Biosynthetic Pathway and Porphyria Treatment. In the mitochondria, glycine and succinyl-CoA are converted to δ-aminolevulinic acid (ALA) by δ-aminolevulinic acid synthase (ALAS1), the rate-limiting enzyme in the pathway; all enzymes are blue. In the cytoplasm, ALA is metabolized to porphobilinogen (PBG) and then to heme; when an enzyme in this pathway is deficient, ALA and PBG accumulate and have neurovisceral effects causing porphyrias (red), including acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and 5-ALA-dehydratase (ALAD)-deficiency porphyria (ADP). Currently used treatments (dark green) decrease ALAS1 activity by inhibiting production (givosiran) or suppressing induction (heme, glucose) of ALAS-1. Investigational treatments (light green) are being developed to replace PBG deaminase (PBGD) activity.

Acute Porphyria Attacks

Acute neurovisceral attacks are usually heralded by prodromal symptoms of brain fog, anxiety, and restlessness followed by visceral or extremity pain, nausea and vomiting, and dysautonomia.2 The sympathomimetic stage can lead to vasospasm of major arteries resulting in myocardial infarction, amaurosis fugax, reversible cerebrovascular syndrome (RCVS), or posterior reversible encephalopathy syndrome (PRES). Fortunately, most attacks do not progress beyond this stage when diagnosed and treated in a timely manner. Attacks that go unrecognized, however, may progress to a fatal neuropathy.

Porphyric neuropathy (PN) is a motor-predominant axonal neuropathy that begins symmetrically in the upper extremities, followed by lower-extremity involvement. Proximal muscles are more often affected, and PN can progress rapidly to quadriparesis and respiratory involvement that can be fatal if untreated. A less common pattern is a focal motor neuropathy presenting with wrist and/or foot drop.3 Numbness over the trunk and thigh and, less commonly, paresthesias in distal extremities can occur; however, sensory symptoms are less common. Because of the acute onset and rapid progression with associated dysautonomia, PN often is misdiagnosed as Guillain-Barré Syndrome (GBS), delaying appropriate treatment for porphyria. Key differences of PN compared with GBS include axonal rather than demyelinating features, the absence of albuminocytologic dissociation in cerebrospinal fluid (CSF), and lack of response to immunotherapy. Symptoms that warrant consideration of an AHP are listed in the Box.1

Diagnosis

The key to early diagnosis is appropriate inclusion in the differential diagnosis and testing a single random urine sample for ALA, PBG, and creatinine levels. A PBG level 4 times the upper limit of normal is diagnostic of AHP and should prompt therapy. A 24-hour urine collection is unnecessary, can be difficult to collect and process correctly, and can delay diagnosis. Although urine porphyrins also are elevated during acute AHP attacks, these are nonspecific and must be collected simultaneously with ALA and PBG to avoid misdiagnosis. Further tests to quantify levels of urine ALA, PBG, and porphyrin levels in plasma, urine, and feces can determine the specific type of AHP. Genetic testing aids in confirming the specific diagnosis and identifying at-risk family members.

Treatment

Attack Prevention

Approximately 3% to 8% of people with AIP, often perimenstrual women, have recurrent severe attacks.2 Preventive therapy of frequent attacks includes prophylactic intravenous (IV) heme (once weekly), ALAS-1 mRNA antagonists, and identification and elimination of precipitants (Table 1).

Intravenous Heme. Within 3 to 4 days of administration, IV heme normalizes ALA and PBG levels by suppressing hepatic ALAS1 induction.4 Although it is an “off-label” use, a single prophylactic treatment 1 to 4 times / month of 3 to 4 mg / kg of IV heme can prevent recurrent attacks.5 To prevent thrombophlebitis and coagulopathy, reconstitution of hematin with 25% human albumin and administration into a larger peripheral or central vein are recommended.6 Other less common side effects of heme include fever, malaise, hemolysis, anaphylaxis, reversible acute renal tubular damage, and circulatory collapse.6,7 Repeated heme administration has been associated with iron overload and tachyphylaxis.

Givosiran. A small inhibitory RNA (siRNA), givosiran silences ALAS-1 mRNA with subsequent inhibition of translation and expression of the ALAS1 protein. Lower levels of ALAS1 reduces levels of neurotoxic ALA and PBG.1 Givosiran was approved by the Food and Drug Administration (FDA) for treatment of AHPs in late 2019.8 The approved dosage of subcutaneous givosiran is 2.5 mg / kg once monthly. A missed dose should be administered as soon as possible, followed by monthly injections thereafter. An expanded access program is also available.

In a phase 3, double-blind placebo-controlled multicenter trial (n=94), participants with a history of recurrent AHP attacks (≥2 in the 6 months before enrollment) givosiran (2.5 mg / kg monthly) treatment resulted in a 73% reduction in mean annualized attack rate compared with placebo treatment. More participants treated with givosiran had no attacks compared with those who received placebo (50% vs 16%). For those treated with givosiran, there was a 77% mean reduction in IV heme use and sustained lowering of urinary ALA (86%) and PBG (91%) levels from baseline, greater reductions in daily worst pain, lower analgesic use, and improved quality of life9,10 compared with those receiving the placebo.

The most common adverse reactions to givosiran are nausea, injection site reactions, rash, and fatigue. Concerns regarding long-term use of givosiran include the possibility of hepatic or renal toxicity as elevated alanine transaminase (ALT), increased creatinine levels, and reduced estimated glomerular filtration rate (eGFR) have been seen. Repression of ALAS1 synthase in the liver also leads to downregulation of some cytochrome-P50s, especially CYP1A2 and CYP2D6; genotyping of cytochromes can be considered prior to treatment and care used in treating anyone with those cytochrome isotypes. Adverse developmental outcomes were seen in animal studies and givosiran has not been tested in pregnant women. The high annual cost (wholesale annual cost=$575,000) may also present barriers to the use of givosiran.

Liver Transplant. A liver transplant (LT) provides nonmutant (wildtype) DNA to correct the genetic defect and restore functional enzyme for the heme pathway, resulting in normal PBG and ALA levels within 24 to 72 hours. An LT often results in clinical remission and has proven efficacy for refractory AIP. However, LT should be considered only as a last resort for those with severe and recurrent attacks not controlled with other treatments.11 An LT has been performed in people with AIP and in 1 person with VP with great success; no persons with HCP have been treated with a liver transplant to date. A single individual with ADP reated with an LT had complications of the procedure that resulted in eventual death.12

Hormone Therapy. Some women with AHP develop cyclic attacks coinciding with the progesterone surge of the luteal phase of their menstrual cycles. These attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue or a low-dose estrogen-progestin combination contraceptive.13

Identifying and Eliminating Precipitants. High-dose oral contraception, some antibiotics (eg, erythromycin, trimethoprim, and rifampicin), anticonvulsants (eg, barbiturates, carbamazepine, phenytoin, and valproic acid), excess alcohol, smoking, fasting, infection, and stress are common precipitants of AHP attacks. A useful list of medications that precipitate attacks is available from the American Porphyria Foundation (www.porphyriafoundation.com/drug-database) and on a mobile app at www.porphyriadrugs.com). Extreme dieting should be avoided and a well-balanced diet with ample carbohydrates (60%-70% of total calories) is recommended.

Acute Attack Treatments

Treatment of an acute attack (Table 2) includes discontinuing potential triggers, providing symptomatic treatment, and using therapies to downregulate hepatic ALAS1. Milder attacks can be managed at home using narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and increased glucose intake to avoid visits to the emergency department (ED). Appropriate diagnosis and prompt specific treatment are often delayed or not provided at all and individuals may be labeled as “drug-seeking” because of frequent visits to the ED for pain. When visceral or extremity pain becomes severe or when neurologic complications ensue, hospitalization is necessary. Bulbar involvement and arrhythmia require close monitoring in intensive care units (ICUs).

δd-Aminolevulinic Acid Synthase-1 Downregulation. Both IV heme and high-carbohydrate loading can be used to downregulate ALAS1. The IV heme treatment is more potent than glucose, decreasing ALA and PBG within 3 to 4 days to result in clinical improvement within 4 days.4 The standard regimen for an acute attack is 3 to 4 mg / kg / day given as a 30-minute infusion into a larger peripheral or central vein for 4 to 14 days depending on a person’s clinical status. This treatment is the safest to use during pregnancy, and early use prevents neuropathy progression.6,14

Glucose inhibits the induction of ALAS-1 and thereby reduces theproduction of ALA and PBG; however, the effect of glucose is weak. Carbohydrate loading can be considered for milder attacks (eg, without paresis, seizure, or hyponatremia) or when an IV heme preparation is not available. Carbohydrate loading is most effective when a dietary restriction has contributed to the attack and can be administered as a high-carbohydrate diet, glucose tablets, or oral dextrose solutions if tolerated. Treatment with IV glucose (300-500 g / day as 10% dextrose in sterile water or 0.45% saline) is also an option.15 Blood sugar and electrolyte levels should be monitored, and infection ruled out. If glucose infusions do not result in clinical remission in 1 to 2 days or if the attack continues to worsen, heme should be administered.

Symptomatic Treatments. See Table 3 for symptomatic treatments.16-19 Early rehabilitation should be considered for individuals with AHP who develop weakness. Close monitoring of respiratory, speech, and swallowing function is essential.

Elimination of Precipitating Factors. A thorough history to identify potential precipitants (medication, alcohol use, smoking, recent weight changes) of an acute attack should be considered. Any infections should be treated promptly.

Investigational Treatments

Replacement of deficient enzyme, mRNA, and DNA are emerging therapies being studied with promising but as yet unproven results.

Protein Replacement. Selective administration of recombinant human PBG deaminase (rh-PBGD) in animal models lowers plasma PBG levels, providing proof of concept for this approach.20 Pharmacokinetic and pharmacodynamic studies of rh-PBGD-enzyme replacement in people with AHP who were asymptomatic transiently lowered PBG for 2 hours.21 More studies are required to determine dose, safety, and efficacy for use to treat AHPs.

Transcript Replacement. Human-PBGD (hPBGD) mRNA encapsulated in lipid nanoparticles administered via IV-induced dose-dependent protein expression in mouse hepatocytes and rapidly normalized urine ALA and PBG excretion in ongoing attacks. Multiple administrations to nonhuman primates suggest that the hPBGD, selectively targeted to hepatocytes, may prove effective in the treatment of AIP.22

Gene Replacement. Liver-directed gene therapy using an adeno-associated virus (AAV)-vector encoding PBGD in mouse models of AIP restored normal hepatic-PBGD activity and prevented acute attacks. A phase 1 study in individuals with AIP who had frequent attacks was safe and improved symptoms and quality of life of some participants but failed to reduce porphyrin precursors levels, likely because of insufficient liver transduction at the doses tested.23 Another approach using nonviral gene delivery of plasmids encoding PBGD in human and mouse PBGD-deficient fibroblasts resulted in a high expression of functional PBGD.24

Conclusion

Timely diagnosis, prompt treatment, and elimination of potential precipitants can prevent neurologic complications of AHP. Understanding genetic abnormalities and pathogenesis of porphyria has opened new avenues in the management of porphyrias. Givosiran, a small interfering mRNA therapy, represents a novel and targeted treatment approach and is the only FDA-approved treatment for the prevention of recurrent disabling attacks. Whether givosiran may also be effective for treating acute attacks requires further study. The delivery of rh-PBGD enzyme or its mRNA is under study for new therapeutic approaches for AIP, to restore levels of PBGD protein, and has shown promising results in animal models. More studies of protein, mRNA, and DNA replacements are required to assess their efficacy in AHP patients.

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VBP reports no disclosures
RGM has participated on a medical advisory board with Alnylam and Argenx Pharmaceuticals
HLB is principal investigator for clinical research studies funded by Alnylam Pharma, Gilead Sciences, and Mitsubishi-Tanabe, North America (funding of which goes to Wake Forest University) and has served as a consultant to Alnylam, Mitsubishi-Tanabe, and Recordati Rare Chemicals in the last 3 years