Continuing Education Activity

Acute intermittent porphyria is a rare autosomal dominant disease characterized by a deficiency of hydroxymethylbilane synthase (HMBS). It presents with abdominal pain, nausea, vomiting, peripheral neuropathy, and seizures. Treatment for acute attacks is intravenous heme. Definitive treatment is an orthotopic liver transplant. This activity gives an overview of the etiology, clinical presentation, evaluation, management, and treatment of the disease by an interprofessional team.

Objectives:

• Identify the etiology of acute intermittent porphyria.
• Review the evaluation of acute intermittent porphyria.
• Outline the management approaches and therapeutic options available for acute intermittent porphyria.
• Describe interprofessional team strategies for improving care coordination and communication to advance early diagnosis and management of acute intermittent porphyria and improve outcomes.

Introduction

'Porphyria' has been derived from the ancient Greek word porphura, meaning purple. Porphyrins are precursors of heme, an essential component of hemoglobin. Each subunit of hemoglobin is a globular protein containing an embedded heme group that contains one iron atom, capable of binding one oxygen molecule. The heme synthesis pathway is a multi-step process that involves a specific enzyme at every step. Thus, porphyrias are distinct clinical syndromes, which arise due to deficiency or defect in a particular enzyme needed for a specific step of the heme synthesis pathway. Although these syndromes have conventionally been classified depending on the predominant system involved (cutaneous vs. neurohepatic), significant overlap occurs, and many porphyrias present with mixed symptoms.

The clinical presentation, severity, and prognosis of individual porphyrias depend on which enzyme is deficient and the corresponding heme precursor or porphyrin accumulation. Acute intermittent porphyria (AIP) ranks as the most common and severe form of acute porphyria. Other acute porphyrias include hereditary coproporphyria (HCP), variegate porphyria (VP), and 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria (Doss porphyria).[1]

Similar to the majority of porphyrias, AIP shows an autosomal dominant pattern of inheritance. Acute porphyrias like AIP characteristically demonstrate acute episodes of neurovisceral symptoms but may not manifest fully for a long time. AIP manifests as episodes of abdominal pain, neuropathies, and constipation, but, unlike most other porphyrias, patients with AIP do not develop a cutaneous rash. The primary enzymatic defect in AIP is the deficiency of porphobilinogen-deaminase, also called hydroxymethylbilane synthase (HMBS), the third enzyme in heme synthesis. The acute attacks of AIP are a result of the uncontrolled upregulation of the ALA synthase enzyme. The diagnosis of AIP gets delayed due to nonspecific symptoms and similarities with other diseases. The only cure is orthoptic liver transplantation.[2][3]

Etiology

Acute intermittent porphyria results from mutations in the HMBS gene, which causes about 50% of HMBS deficiency. The gene is on the 11q24.1-q24.2 chromosome. For now, there are known 391 HMBS gene mutations.[4] This deficiency is noticeable in the acute attacks, where the heme pool in the liver gets used, and there is the induction of delta-aminolevulinic acid synthase (ALAS1). This process leads to delta-aminolevulinic (ALA) accumulation and porphobilinogen (PBG), which are the immediate precursors proximal to the HMBS.[3] 

Inducers of acute attacks are alcohol, infections, low caloric intake, reproductive hormones change, and high-risk porphyrogenic drugs. The Norwegian Porphyria Centre (NAPOS), with the European Porphyria Network (Epnet), has created a list of medications that clinicians must avoid using in porphyria patients. These drugs include ketamine, thiopental, chloramphenicol, erythromycin, nitrofurantoin, rifampicin, trimethoprim/sulfamethoxazole, spironolactone, methyldopa, valproic acid, carbamazepine, phenytoin, phenobarbital, primidone, and risperidone.[5]

Epidemiology

Estimates of the combined prevalence of acute porphyrias are 5 cases per 10000 persons. Out of all these clinical syndromes, porphyria cutanea tarda (PCT) that has prominent cutaneous features, is the most common porphyria, with an estimated prevalence of 1 in 10000. AIP, the most common acute porphyria, has an overall European prevalence of approximately 1 in 2000, with a higher incidence of 1 in 1000 in Sweden due to the founder effect. Recently, there are also reports of the founder effect correlating with a higher prevalence of AIP in certain ethnic groups in Argentina and Spain.[6][7]

Acute intermittent porphyria is a low-penetrant genetic metabolic disease with penetrance considered to be around 10% to 20%.[8] Excepting specific AIP populations, the penetrance of AIP in the general population has been estimated to be less than 1%.[9] Manifest AIP (MAIP) is considered when carriers develop typical acute neurovisceral attacks with an elevation of porphyrin precursors. In the absence of clinical episodes, it is referred to as latent AIP (LAIP). Although higher penetrance has links to specific mutations, the overall genetic susceptibility factors underlying penetrance remain unknown.

Acute intermittent porphyria affects women to a greater degree than men, with a ratio of between 1.5 and 2 to 1. Attacks are rare before puberty. The typical age for the appearance of symptoms is between 18 to 40 years.

Pathophysiology

Acute attacks of acute intermittent porphyria are more frequent in women, especially in the post-pubertal age group. The acute attacks of AIP are typically triggered by certain factors, which include several drugs, infection, fasting, alcohol, steroid hormones, as stated above.

In acute intermittent porphyria, the neurologic damage occurs due to the accumulation of the porphyrin precursors, porphobilinogen, and aminolevulinic acid (ALA). The AIP-associated neurological damage manifests as peripheral and autonomic neuropathies and psychiatric manifestations.

The exact mechanism by which elevated levels of porphobilinogen and ALA lead to symptomatic disease remains enigmatic because most patients with the genetic defect do not present with symptoms despite excessive porphyrin secretion.

A recent (2017) case-control study in 50 patients reported the association of acute intermittent porphyria with systemic inflammation. Storjord et al. found that the levels of insulin, C-peptide, prealbumin, and markers of kidney function, were decreased in symptomatic patients only, sparing the asymptomatic ones. They postulated that in symptomatic patients of AIP, reduced insulin release is associated with enhanced disease activity and compromised kidney function.[10]

History and Physical

Acute attacks of acute intermittent porphyria usually last for up to a week. 

The symptoms progress as follows:[6] Abdominal pain, then psychiatric symptoms, and finally peripheral neuropathies. 

The abdominal pain is typically severe, epigastric, and colicky. It tends to last for several days. It can be associated with constipation and vomiting.[11]

Patients can present with a broad spectrum of psychiatric symptoms, such as depression, which are accompanied by concurrent abdominal and/or neurologic symptoms. A study conducted in Sweden demonstrated an increased risk of schizophrenia or bipolar disorder in patients with AIP, as well as in their relatives. [12]

Peripheral neuropathies can manifest as a weakness that begins in the lower extremities and ascends, although any nerve distribution may be affected. This presentation can mimic Guillain-Barre syndrome (GBS). Hypertension and tachycardia secondary to autonomic neuropathies can also occur.

Central nervous system signs may include delirium, weakness with progression to quadriplegia and respiratory failure, cortical blindness, and even coma. In 5% of cases, patients can develop seizures, with partial seizures being the most common subtype.[13] Sometimes red or brown urine may be observed, which darkens on exposure to air, light, and warmth. It is important to note that, unlike porphyria cutanea tarda, AIP does not have any cutaneous manifestations.

In conventional terms, patients have been reported to be completely free of symptoms in between the attacks. However, it is also suggested that 20% to 64% of patients may suffer from disabling chronic manifestations such as pain, nausea, fatigue, and neuropathic features, including numbness and tingling sensations.[14]

Evaluation

The diagnosis of acute intermittent porphyria results from finding elevated PBG in urine in a random sample kept protected from light. Diagnostic confirmation should include quantitative measurement of PBG, ALA, and total porphyrins from the same urine sample. Normal values are 0 to 4 mg/L, but values may reach as high as 25 to 100 mg of ALA and 50 to 200 mg of PBG during an acute attack of AIP.

A urinary PBG level of only 0 to 4 mg/L during acute symptoms almost rules out acute porphyria as the cause of neurovisceral symptoms.

Although urine collection for quantification of PBG and ALA is optimal during the peak of an attack of AIP, it may be collected within a few days to weeks after the acute episode also, owing to the persistent elevation of urinary ALA and PBG for many months to years after an attack.[15] The only exception to this leniency is the timed collection of urine, which arises if the patient has received treatment with a 4- to 5-day course of intravenous heme.[1]

Elevation of urine porphyrins, especially copro porphobilinogen (caused by spontaneous polymerization of porphobilinogen in the urine), is often observable. However, it merits noting that the nonspecific elevation of urine porphyrins, especially coproporphyrins (1 to 2 times the reference range), is common and not specific for porphyria. Stool porphyrins are typically within the reference range or just mildly elevated.

An increase in plasma porphyrin confirmed by increased fluorescence emission scan peak at 619 nm can present. Molecular and DNA testing of HMBS deficiency is unnecessary for the diagnosis but has utility for family screening.[16][11][17]

Associated Laboratory Abnormalities (During An Acute Attack):

• Hyponatremia - most common
• Hypomagnesemia is also common
• Mild aminotransferase elevations 
• Mild leucocytosis

Differentiating Between Acute Porphyrias

As mentioned below (vide infra), most acute porphyrias' symptomatology shows significant overlap. Symptoms of AIP are often clinically indistinguishable from those of hereditary coproporphyria and variegate porphyria. Although the diagnostic approach to distinguish AIP from other acute porphyrias has little evidence backing at present, new evidence-based diagnostic strategies are under development for these conditions. 

Plasma Fluorescence Staining

In contrast to AIP, HCP, and other porphyrias in which the sera of subjects with biochemically active disease have emission peaks at approximately 619 nm to 620 nm, the serum from patients with VP have a unique porphyrin-peptide in plasma that has its peak fluorescence at approximately 626 nm, following excitation by light of 410 nm (the Soret band). This reaction forms the basis of the utility of fluorescence of diluted sera at physiologic pH to differentiate VP from other acute as well as cutaneous porphyrias.[18]

Emerging Role of Genetic Mutation Analysis in Diagnostic Confirmation 

The specific type of acute porphyria is now discernable by genetic testing, which is available commercially at several labs. The approach involves sequencing of the four genes that are defective in the acute porphyrias:[1]  

Gene/Type of Acute Porphyria  

• ALAD/ALAD-deficient porphyria (Doss porphyria)  
• HMBS/AIP  
• CPOX/HCP  
• PPOX/VP  

The evolution of next-generation sequencing (NGS) to porphyria diagnosis is ongoing, with investigators having recently designed a panel containing four genes - ALAS1, HMBS, CPOX, and PPOX for mutational analysis of AIP, HCP, and VP.[19]

Treatment / Management

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]

Differential Diagnosis

In an observational study of acute porphyrias, which included 90 patients with AIP, researchers found that the diagnostic delay was a mean of 15 years.[31] The predominance of the acute abdomen as the presenting symptom of an acute attack of AIP, patients often undergo appendectomies or cholecystectomies before the diagnosis of porphyria is suspected and/or confirmed. 

Owing to the broad spectrum neuro-visceral clinical presentation of AIP, the list of differential diagnosis is long: 

1. Other acute porphyrias - Clinically, it is often difficult to differentiate from other acute porphyrias: HCP, VP, and Doss porphyria.
2. Causes of acute abdomen - Peritonitis, appendicitis, acute cholecystitis, acute gastritis, acute pancreatitis, intestinal occlusion, strangulated abdominal hernia, acute mesenteric ischemia, ileus, diverticulitis, esophagitis, endometriosis, gastric outlet obstruction, intussusception, pelvic inflammatory disease, ovarian cysts, acute pyelonephritis, aortic dissection.
3. Lead poisoning constitutes a substantial differential, and one must look for the presence of anemia and lead levels in the blood to confidently differentiate between the two conditions.[11] 
4. Causes associated with clinical features of autonomic neuropathy - Hypertensive crisis, tachyarrhythmias,  adrenal crisis, familial Mediterranean fever, fibromyalgia
5. Neuropsychiatric simulators - Acute psychotic attack, delirium, panic attack, Guillain-Barre syndrome.

Prognosis

Prognosis is good if acute intermittent porphyria is recognized early and treated at the time. The mortality has decreased through the past decades to 5% to 20% (on acute attacks) thanks to new methods of diagnosis and treatment. But if the disease is resistant to heme therapy and is recurrent, the only currently approved way to reduce mortality is with an orthotopic liver transplant.[17][2][1]

With ongoing trials exploring the efficacy and safety of ERT and liver gene therapy, the prognosis of AIP is expected to become better very soon.

Complications of acute intermittent porphyria (vide infra); arterial hypertension, chronic kidney disease, neurologic deficits, and risk of hepatocellular carcinoma must remain in check by ensuring close observation and review of the patient.

Complications

1. Systemic arterial hypertension and chronic kidney disease - Reports exist of the prevalence of up to 30% of these closely linked disorders in patients with AIP.[32] End-stage renal disease (ESRD) is a life-threatening complication in AIP patients with chronic active disease.[33]
2. Muscle denervation is another major pathologic complication.[6] Some patients after acute attacks have residual deficits such as foot/wrist drop or wasting of the intrinsic muscles of hands.[17]
3. Hepatocellular carcinoma (HCC): This is the most deadly long-term complication of AIP.  Results of studies performed over the last 3 to 4 decades have shown a remarkably increased incidence of HCC in AIP patients compared with the general population.[34] A Swedish study showed that the risk for HCC in AIP is increased 80 times after the age of 50 years.[11][35] It is worthwhile to know that AIP-associated HCC is typically free from the usual preceding comorbidities such as Hepatitis B or C infection.

Deterrence and Patient Education

AIP is a rare autosomal dominant condition that runs a chronic course with recurrent acute episodes of neurovisceral symptoms. Trials are giving hope to find a definitive cure to this life -long disease. Once the diagnosis of AIP or some other acute hepatic porphyria is confirmed, patients should be thoroughly counseled and provided with the list of trigger factors (that can precipitate an attack) for avoidance, especially drugs that are safe and unsafe. They should know that treatment is only available for acute attacks and that the best way to remain asymptomatic is by preventing precipitants. If they have abdominal pain should go immediately to the emergency department. They should receive education on prognosis and complications and are strongly encouraged to obtain genetic testing done for their offspring.

Enhancing Healthcare Team Outcomes

Clinicians should suspect acute intermittent porphyria should in patients with abdominal pain, and symptoms or signs suggestive of neuropsychiatric morbidity. A patient with a purely medical ailment often ends up with the surgeons due to recurrent acute abdomen and may undergo unnecessary surgeries. Thus, the surgical team should be aware of this non-surgical cause of severe acute abdomen and maintain a high index of suspicion in a patient with recurrent attacks or one who presents with additional neuropsychiatric symptoms.

Interprofessional involvement of the primary care physician, nurse practitioner, metabolic/genetic disease expert, hematologist, biochemist, pharmacist, nursing, and the surgeon is essential to diagnose the disease early to limit the long-term complications of the patient. Lastly, the involvement of clinical geneticists for genetic counseling regarding the conception of a child by a patient with AIP is paramount to discuss the risk of acquisition, prenatal testing, and other aspects of prevention and/or early identification of AIP carrier state in the offspring. Nursing will be responsible for heme therapy administration and should monitor therapy progress as well as any adverse reactions, and inform the clinician should there be an issue. Pharmacists should verify dosing, as well as perform medication review to scan both for drug interactions, as well as drugs that can precipitate porphyria attacks, reporting any concerns to the team physicians managing the case. Open communication and collaboration between interprofessional members of the team are essential if one wants to avoid the high morbidity of this disorder. [Level V]