Porphyria is a rare disease caused by a deficiency of enzyme activity in the heme synthesis pathway. According to the location of porphyrin, it can be divided into two categories: erythropoietic porphyria and hepatic porphyria. Hepatic porphyria is caused by a disorder of intrahepatic porphyrin metabolism, often accompanied by liver damage, resulting in an acute attack. Acute hepatic porphyria (AHP) has complex and diverse manifestations, which not only reduces the quality of life, but even endangers life, and long-term recurrent symptomatic attacks can also develop into primary liver cancer, hypertension and renal failure. This article will provide an overview of the treatment of AHP and focus on the new therapies and their research progress, hoping to provide a reference for medical personnel in the treatment of this disease.
1AHP Overview
AHP is a group of diseases caused by liver enzyme deficiencies that cause abnormalities in the heme biosynthesis and metabolism pathway, and porphyrin precursors accumulate in the body, causing a series of non-specific manifestations. AHP includes four types of acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variant porphyria (VP), and δ-aminolevulinic acid dehydrase deficiency porphyria (ADP) (Fig. 1). AIP is the most common form of AHP and is characterized by abdominal pain, neurologic symptoms, and psychiatric disorders, and in severe cases, respiratory paralysis and coma. HCP and VP are mixed porphyrias, and in addition to acute neurovisceral symptoms, skin photosensitivity symptoms can occur. ADP is an extremely rare form of porphyria, characterized by symptoms of acute porphyria, such as abdominal pain, muscle weakness due to motor neuropathy, and neuropsychiatric manifestations without cutaneous manifestations.
Fig.1 Heme synthesis and treatment of AHP
2AHP conventional therapy
The main manifestation of AHP is recurrent acute symptomatic episodes caused by the upregulation of δ-aminolevulinic acid synthase-1 (ALAS1), and avoidance of triggers is one of the primary factors. Treatment begins with the avoidance of any drugs that can cause porphyria flare-ups, and specific drugs can be treated under the guidance of the Porphyrin Drug Network (http://porphyriadrugs.com/). For mild patients, oral high-sugar food can be used, and severe patients are often given intravenous glucose infusion (300~500 g/d), but the effect of this method is relatively weak, and it cannot prevent acute attacks. Heme is a specific drug recommended by foreign guidelines, but due to the slow onset of the drug, it is recommended that venous heme therapy should be given immediately in severe acute attacks, which is safe and well tolerated except for occasional headache and fever, and can also be used for pregnant patients. Studies have found that prophylactic heme transfusion can reduce the incidence of acute attacks of AIP and improve the quality of life of patients, but complications such as infection, venous thrombosis, and iron overload will occur, and the efficacy of repeated infusion will be reduced, so the clinical application of heme should be well indicated.
3AHP New Therapy
3.1 RNAi therapeutics
RNAi therapeutics utilize small RNA molecules (miRNAs and siRNAs) to form RNA-induced silencing complexes to enable post-transcriptional gene regulation that interferes with specific gene expression. Givosiran is a newly developed siRNA-related drug that binds to and silences ALAS1 mRNA in hepatocytes, thereby reducing ALAS1 expression and reducing δ-aminolevulinic acid (ALA) and porchogen production, both of which are effective in AHP induced by ALAS1 upregulation. Preclinical studies have found that administration of siRNA to AIP mice reduced ALAS1 expression and porphyrin levels, and prophylactic use of siRNA inhibited phenobarbital-induced exacerbations. Phase I clinical trial (NCT02452372) found that once-monthly injections of Givosiran induced ALAS1 mRNA downregulation, resulting in neurotoxic ALA and porchogen levels close to normal, reducing the rate of attacks, and subsequent phase III multicenter, placebo-controlled, randomized double-blind clinical trials (NCT03338816) found that compared with the placebo group, Givosiran reduced urinary porphyrin levels, reduced the number of days of heme use, and improved daily pain scores, The rate of acute exacerbations was reduced by 74%. Based on encouraging Phase III results, Givosiran was approved by the U.S. Food and Drug Administration in November 2019 for the treatment of AHP in adults, recommending 2.5 mg/kg subcutaneously once a month. It was approved by the European Medicines Agency in January 2020 for the treatment of AHP in adults and adolescents aged 12 years and older. A recent study of the pharmacokinetics and pharmacodynamics of this drug showed that 2.5 mg/kg had the best efficacy. The final results of the recently reported Givosiran Phase III clinical trial suggest that long-term monthly treatment with Givosiran can sustainably improve the clinical performance and quality of life of AHP with a favorable safety profile. However, treatment with Givosiran may increase hepatic and renal adverse events, requiring close follow-up of liver enzymes, renal function, lipase, and homocysteine. As a result, the European Medicines Agency recommends reducing the dose to 1.25 mg/kg once a month if there is a dose interruption in patients with severe or clinically significant transaminase elevations.
3.2 Enzyme replacement therapy
Enzyme replacement therapy refers to a treatment that replaces missing enzymes in a patient's body with exogenous enzymes. Hydroxymethylcholin synthetase (HMBS) enzyme replacement therapy is currently in the preclinical research stage of AIP. Intravenous infusion of human HMBS enzyme to replace inactivated wild-type HMBS enzyme can reduce the concentration of urinary porphyrin in patients with AIP. However, clinical benefit has not been demonstrated in follow-up trials, possibly because hepatocytes cannot be targeted. Recent experiments have shown that intravenous infusion or subcutaneous injection of the recombinant protein in mice can alleviate acute attacks in mice, increase hepatocyte HMBS activity, and found that the drug can last for up to 6 days in serum, indicating that it has a protective effect against chronic symptoms, no immunoallergic reaction or antibody formation, and its safety has been confirmed after multiple administrations. rhApoA1-HMBS is still in the preclinical research stage, which requires further clinical trials, and the production cost is high, and there is still a lack of large-scale production technology.
3.3 Gene Supplementation Therapy
This strategy is to use gene transduction technology to transduce the correct HMBS DNA or mRNA into hepatocytes and make them express normally, in order to restore the expression of HMBS. The method is still in preclinical studies for AIP. The main challenge is to choose a suitable, safe and efficient carrier. Recombinant adeno-associated virus (rAAV) has been found to be safe and effective. Studies in mice and non-human primates have found that rAAV2/5-HMBS achieves highly efficient and homogeneous hepatocyte transduction, which can re-establish hepatic HMBS activity and prevent acute attacks in experimental subjects. In the follow-up phase I clinical trial (NCT02076763, NCT02082860), each injection of 5×1011~1.8×1013 genomic copy number/kg of the vector, it was found that rAAV2/5-HMBS administration was safe, but the dose did not achieve metabolic correction of AIP, and the porphyrin level did not change, although the effectiveness of the study did not get the expectation, there was still a positive impact: the therapy was safe, and the number of hospitalizations and heme therapy had a tendency to decrease, After 1 year of treatment, vector genome and transgene expression can be detected in the liver. The efficacy of AAV-gene therapy vectors has been improved by constructing highly functional bioengineered HMBS variants and has shown desired results in HMBS-deficient mice. With regard to mRNA augmentation, lipid nanoparticles have been used as effective carriers for inborn metabolic disorders. Through preclinical experiments, it was found that after intravenous injection of lipid nanoparticle-encapsulated rhHMBS mRNA, the activity of hepatocytes HMBS increased rapidly and uroporaline precursors were rapidly normalized in acute AIP mice, and the safety of the drug was confirmed and expressed in vivo after multiple administrations to non-human primates, indicating that the drug can prevent the occurrence of chronic complications.
3.4 Drug chaperones
The stability of enzymes during heme biosynthesis is of great significance for maintaining their specific functions. In one study, the compound 5-[(2-chlorophenyl)methyl]-2-hydroxy-3-nitrobenzaldehyde was found to act as a drug chaperone for stabilizing HMBS, and oral administration of this compound in AIP mice increased the stability and total enzyme activity of hepatic HMBS and decreased the concentration of intrahepatic porphyrins during acute attacks. Pharmacochaperone therapy can be a promising treatment option for AIP, which does not produce an immune response compared to gene and RNAi therapies and can be used as a prophylactic and interventional treatment during acute porphyrin attacks. However, targeting is not currently possible, and this long-term non-specific inhibition may lead to serious adverse toxic effects.
4 Glycine transporter (GlyT) inhibitors
Glycine is an important precursor for heme biosynthesis and a substrate for the rate-limiting enzyme ALAS1. One study found that the GlyT2 inhibitor Org25543 prevented the accumulation of porphyrinogen IX in a cell model of erythropoietic protoporphyria, a phenomenon also found in primary erythroid cultures of CD34+ progenitor cells from patients with erythropoietic protoporphyria. Therefore, inhibition of glycine uptake may be an effective target for the treatment of heme synthesis disorders, but this method currently lacks a targeted effect, and has not yet been verified in hepatocytes, and needs to be continuously explored.
5Advances in the treatment of AHP-related complications
5.1 Hyponatremia
Hyponatremia occurs during an acute attack of AHP and may cause seizures. Studies have shown that the main cause of hyponatremia during AHP may be due to antidiuretic hormone dysregulation syndrome (SIADH). The first-line treatment for SIADH is fluid restriction, but fluid restriction is not easy to achieve in patients with AHP who require glucose infusion, and sodium replacement in the setting of hyponatremia remains a challenge because intravenous dextrose can lead to increased total fluid intake and further exacerbate hyponatremia. If sodium supplementation can be taken orally, 5~8 g of NaCl can be supplemented in two times; For intravenous infusion, correction with 3% NaCl is recommended, starting at 10 mL/hour and increasing to 50 mL/hour depending on symptoms; Monitor the serum sodium closely every 2~4 h, and suspend the infusion when the serum sodium reaches 126 mmol/L or increases >5 mmol/L in one day. Patients with AHP usually have hypertension, excessive sodium supplementation can cause pulmonary congestion or hypoxemia, and most deaths during an acute attack of porphyria are associated with hypoxemia, so it is important to determine whether hypoxemia occurs when correcting hyponatremia. Tolvaptan is a selective antidiuretic hormone receptor antagonist that inhibits tubular reabsorption of water, produces a diuretic effect without altering Na+ balance, and is used in the acute phase of AHP, and is recommended to be taken orally in the morning, starting with 7.5 mg, with dose adjusted according to response. When the serum sodium rises to 132~140 mmol/L, the use of tolvaptan can be suspended. Tolvaptan is not recommended within 24 hours of hyponatremia, and oral salt or 3% NaCl is preferred. Tolvaptan during porphyrin flare-ups has only been reported to be well tolerated in a few isolated cases, but certain criteria are required for its use. Recently, it has been reported in China that tolvaptan treatment in one patient with AIP has acceptable efficacy and no adverse reactions.
In addition, urea is often used as a second-line option for SIADH, but in patients with porphyria who are treated with high glucose and develop glucouria, the concentration gradient between the lumen and the interstitium decreases, and urea therapy is ineffective.
5.2 可逆性后部脑病综合征（PRES）
PRES is a clinicopathological condition caused by the inability of the posterior circulation to self-regulate, with seizures occurring in up to 75% of patients. Treatment includes prompt diagnosis of the cause, treatment of the underlying disorder, control of hypertension, and symptomatic supportive care. There have been case reports of PRES in AIP, followed by intravenous glucose infusion, discontinuation of all anticonvulsant therapy, and subsequent MRI of the head showing the disappearance of signs of PRES, suggesting that the treatment of AIP-induced PRES is largely dependent on the treatment of the underlying disorder.
5.3 Hepatocellular carcinoma and bile duct carcinoma
People with porphyria are at risk of hepatocellular carcinoma or cholangiocarcinoma. Depending on the condition, treatment includes both curative and palliative care. Liver resection, orthotopic liver transplantation, percutaneous local ablation are indicated for patients with early-stage tumors. Liver resection is the most commonly used method for AHP-related liver tumors, which can lead to recurrence and possible death due to complications. Radiofrequency ablation or continuous local therapy with percutaneous hepatic arterial chemoembolization (TACE) is an option for patients with relapse, and periodic TACE therapy is an option for asymptomatic patients. Liver transplantation can be used as a therapeutic option for primary liver tumors in patients with AHP, but it may have long-term side effects and a series of complications due to lifelong immunosuppressive therapy. Patients with advanced hepatocellular carcinoma or those with poorly controlled disease and who do not respond to TACE can be treated with the oral multikinase inhibitor sorafenib, and palliative therapy is used for end-stage hepatocellular carcinoma. Liver ultrasound every 6 months starting at age 50 is recommended for all patients with AHP, regardless of symptom severity.
5.4 Periodontal disease
Analgesics and anesthetics used in dentistry can induce or worsen porphyria, and barbiturates should be avoided. Heavy metals have been shown to inhibit various enzymes in the heme synthesis pathway in animal models and tissue preparations, so AHP patients are advised to avoid the use of alloying components and materials containing precious metals to repair caries. In the treatment of porphyria attacks, it is necessary to pay attention to the maintenance of masticatory function in porphyrin patients, and carry out oral hygiene management according to diet, and follow up every 3~6 months.
5.5 Menstrual cycle-related porphyria
Progesterone and its metabolites have been found to be inducers of ALAS1 enzyme in the liver, and progesterone increases after ovulation, enhancing the activity of ALAS1 enzyme and thus inducing porphyria associated with the menstrual cycle. The main point of treatment for these conditions is to stop the menstrual cycle, but the safety of oral contraceptives in women with AIP has been reported in the literature. Gonadotropin-releasing hormone analogues (GnRH-α) are synthetic hypothalamic analogues, and treatment with GnRH-α has been shown to inhibit endogenous sex hormone production and successfully prevent recurrent episodes of porphyria associated with the menstrual cycle. However, long-term use of GnRH-α is associated with a range of postmenopausal symptoms associated with low estrogen and an increased risk of osteoporosis. Therefore, giving a small dose of sex hormone backfill at the same time as GnRH-α therapy can prevent or effectively alleviate the above symptoms. Although low-dose estrogen and progestogens may be useful in reverse, these patients are sensitive to sex hormones, and the addition of sex hormones may worsen porphyria symptoms, so caution is required with the use of sex hormones.
5.6 Skin photosensitivity
For the skin photosensitivity symptoms of VP and HCP patients, the treatment is mainly light avoidance, and vitamin D supplementation should be routinely supplemented during the light avoidance period. Secondly, melanocortin receptor agonists, antioxidants, and light therapy for skin symptoms have been trialed in clinical practice, while gene therapy for the cause, GlyT inhibitors to reduce the precursor of heme synthesis, and inhibitors of key enzymes for heme synthesis are in the exploratory stage.
6. Summary and outlook
In conclusion, AHP currently involves a multifaceted treatment, and in addition to traditional hyperglycemic therapy and intravenous heme transfusion, more therapies to prevent acute exacerbations are needed clinically. Gene therapies and drug chaperones that are being developed to enhance enzyme stability have great potential for the prevention of AHP. With the improvement of the diagnosis level and the increase of attention to rare diseases in the mainland, the diagnosis and treatment of AHP has been promoted, and it is expected that more treatment methods suitable for AHP in the Chinese population can be explored in the future.
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https://www.lcgdbzz.org/cn/article/doi/10.12449/JCH240430
引证本文 Citation
Advances in the treatment of acute hepatic porphyria[J]. Journal of Clinical Hepatobiliary Diseases, 2024, 40(4): 828-833
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