ALAD Porphyria

The treatment of ALAD porphyria is directed toward the specific symptoms that are present in each individual. Because there have been so few cases of ALAD porphyria, there is only limited information on treatment for the disorder.

Initial And Symptom-Oriented Treatment

Owing to the simulation of symptoms of acute intermittent porphyria by several abdominal, metabolic, and neuropsychiatric conditions, establishing a confirmed diagnosis forms the core of the management of AIP.

Avoidance of precipitants, especially drugs, requires extreme emphasis, ingraining it in the patient and relatives’ psyche. (vide infra)

When a patient with confirmed AIP presents with an acute attack, the usual first approach is to load the patient with a high carbohydrate diet or intravenously administered dextrose to inhibit hepatic ALAS1 transcription. Administration of 10% dextrose in 0.45% saline should start immediately. If the patient does not present with weakness, vomiting, or hyponatremia, a trial of a high carbohydrate diet for 48 hours before starting specific treatment is the current recommendation.[20][13][11]

For pain, parenteral opiates are the best option (morphine, diamorphine, and fentanyl). Nausea and vomiting are controllable with prochlorperazine, promazine, and ondansetron.  These symptoms usually start abating in 72 to 96  hours.[20] For tachycardia and hypertension, preferred medications are beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers (diltiazem). If the patient presents with seizures, they are controllable with diazepam, magnesium sulfate, or clonazepam.[11]

Specific Treatment

Intravenous administration of heme is the specific therapy. It replenishes the hepatocyte heme pool and down-regulates ALAS1, resulting in reduced production of porphyrin precursors and corresponding improvement in symptoms.[21] Heme not only controls hepatic ALAS1 by down-regulating ALAS1 transcription but also by inducing mRNA destabilization or by blocking the mitochondrial import of the mature enzyme.[3]

Owing to the delayed effect of heme therapy on reducing plasma ALA and PBG levels, intravenous heme therapy (IHT) should be administered without delay in severe acute attacks and maintained for four days (3 to 4 mg/kg of heme/day). A response usually appears on the third day with a decrease of urine and serum PBG. Panhematin administration should be through a large peripheral vein or central line due to the risk of phlebitis in small veins, a risk also reduced by preparing it with human albumin instead of water. Other complications are an increase in prothrombin time during the first 2 hours and increased iron production in the liver. Patient discharge can take place when parenteral opioids can stop, and they can tolerate oral drugs.[20]

Excepting occasional complaints of headache or pyrexia, IHT is well tolerated. However, there are inherent risks associated with recurrent treatments with IHT, of which every caregiver should be cognizant.

Risks Associated With Recurrent IHT

The following enumerates the significant issues associated with recurrent IHT – the need to replace the venous access to prevent thromboembolic disease, risk of liver fibrosis, hepatic iron overload, and development of therapeutic ‘tolerance’ to heme infusion. Research has shown that heme infusion can induce the expression of hepatic heme oxygenase 1 (HMOX1, EC 1.14.99.3, HGNC: 5013).[22][23][24] HMOX1 is the crucial enzyme of heme catabolism. Its induction by heme therapy results in the reduction of hepatocyte heme pool and consequently enhanced expression of ALAS1.[25] This heme-induced auto-catabolic effect generates the tolerance reported in some patients.

Currently, the only established cure for acute intermittent porphyria is orthotopic liver transplantation (OLT) with a reported survival rate of around 80%.[26][27] However, a high risk (40%) of hepatic artery thrombosis with OLT prompted the same authors to recommend reserving the procedure for patients with severe recurrent acute attacks and highly impaired quality of life (QoL).

Some studies are looking for other alternatives. These are in different phases of clinical trials, and this CME chapter at present, only seeks to inform the readers of these potential and futuristic therapies:

Potential/Experimental Therapies For AIP

Enzyme Replacement Therapy [ERT] – Based on the experience of administering doses of recombinant human HMBS/PBGD (rhPBGD) protein in a mouse model of AIP that reduced plasma PBG accumulation during an acute attack induced after phenobarbital challenge, in 2002 the European Medicines Agency (EMA) granted recombinant human HMBS/PBGD an orphan designation (EU/3/ 02/103). Researchers conducted clinical trials in healthy subjects, asymptomatic HMBS-deficient subjects with increased porphyrin precursor excretion, and AIP patients with repeated attacks.[28][29] Although the enzyme was able to detoxify PBG metabolites, the treatment approach limitations included its short half-life in circulation and the lack of liver targeting.

Liver Gene Therapy – Clinical trials using two strategies, HMBS-gene therapy and interference RNA for ALAS1 gene inhibition, are being conducted in patients with AIP. The two strategies include  – the delivery of the HMBS gene to the hepatocytes using a viral vector. The other option is a small interfering RNA (siRNA) directed against aminolevulinic acid synthase, with the objective of reducing delta ALA production. Both of them are still in the trial phase and await approval, pending larger trials that would hopefully provide consistent efficacy and safety.[20][30]

Avoidance of triggering factors such as alcohol, certain drugs, fasting, and low carbohydrate diets is recommended for affected individuals. The specific drugs that may need to be avoided in one person can differ from the drugs that need to be avoided in another. More information on these preventive measures and a list of drugs that may potentially need to be avoided are available from the American Porphyria Foundation (see Resources section of this report).

Two standard treatments for acute porphyrias, in general, are intravenous infusions of hemin and supplementation with glucose. However, these therapies have not been universally effective in treating individuals with ALAD porphyria.