Clinical Challenges of Acute Porphyria in the Young Adult

Abstract

Porphyria is a metabolic disorder caused by a mutation in the heme biosynthetic pathway, with vague symptomatology and rare prevalence. A triad of hyponatremia, intermittent seizures, and abdominal pain should raise suspicion for porphyria. The diagnosis is based on increased blood porphobilinogen levels and genetic mutations. Treatment involves Dextrose-10 administration followed by hematin infusions as soon as possible. A maintenance dose of hematin is required in some cases. Here, we report a delayed diagnosis of acute intermittent porphyria (AIP) in an 18-year-old female, who first presented with severe anemia attributed to iron deficiency from menstrual blood loss. After discharge, she was readmitted with bilateral lower extremity and abdominal pain, hyponatremia, and seizure attributed to polypharmacy. During this second hospitalization, she was transferred to our hospital complaining of chest pain, shortness of breath, markedly decreased weakness, dysphagia, and hallucinations. After an extensive workup, she was diagnosed with AIP, and Dextrose-10 and hemin infusion were started. Our patient was found to have a missense mutation in the Hydroxymethylbilane synthase gene. She recovered after an extended ICU stay of 45 days and was discharged with a moderate improvement of weakness. Early diagnosis is necessary to prevent severe manifestations and long-term sequelae, such as axonal neuropathy, which occurred in the presented case.

Introduction

Acute intermittent porphyria (AIP) is a rare metabolic disorder resulting from a mutation of hydroxymethylbilane synthase, or porphobilinogen deaminase (PBGD), along the heme biosynthetic pathway^1,2 (Figure 1). This mutation leaves affected individuals susceptible to precipitating triggers that may exacerbate the altered heme pathway, ultimately leading to the neurovisceral attacks classically found in porphyria. Triggers for the upregulation of the heme biosynthetic pathway include depletion of hepatic free heme, blood loss, certain medications metabolized by P450 enzymes, smoking, alcohol, and caloric restriction. ³ Unfortunately, the American Porphyria Foundation’s registration database is in its infancy and impedes accurate calculation of disease frequency, but gathering from European registries, AIP may occur in the general population with a frequency of 5 to 10 cases per 100 000 patients. ⁴ AIP is also the most common form of porphyria in the US. An overwhelming majority of porphyria cases occur in women during reproductive years, in which acute onset coincides with menses. ²

Figure 1.

Heme biosynthetic pathway. Dysfunction of porphobilinogen, leads to buildup of toxins and acute intermittent porphyria (AIP).

Clinically, the most common symptoms of AIP are nonspecific complaints of abdominal pain and weakness.^4,5 Abdominal signs often present as diffuse cramping pain; however, due to its neurologic origin, most localizing signs, such as rebound tenderness or leukocytosis, are absent.^6-8 Additional symptoms often include the development of tachycardia, hypertension, and electrolyte abnormalities. ⁵ Severe cases may progress to the peripheral, central, and autonomic nervous systems, leading to such sequelae as respiratory failure, psychosis with or without hallucinations, hyponatremia induced seizures, coma, and even death.^4,5

The pathophysiology of neurologic manifestations is not well defined, though there is supportive research suggesting the buildup of heme precursors create a neurotoxic environment. Treatment for AIP involves suppressing the heme biosynthetic pathway (Figure 1) to reduce potentially neurotoxic metabolites and palliation of symptoms during crisis. A more permanent solution is to undergo liver transplantation, which has been shown to be curative. ² In the following patient, administration of Dextrose-10 (D10) was utilized, in addition to hemin infusions, to stop the progression of her disease and begin reversal of her acute condition.

Presentation

An 18 year-old Black female with a past medical history of iron deficiency anemia and menorrhagia transferred to the Neurology floor service after a second admission at an outside hospital in the setting of progressive weakness. The patient reported 5 weeks of abdominal pain, leg cramping, and generalized weakness. During this time, she was found to have a hemoglobin of 4 g/dL, for which she received iron supplementation and 3 units of packed red blood cells (PRBC). The patient’s anemia was attributed to iron deficiency and menorrhagia. She was initially discharged from the outside hospital, but returned 7 days later with complaints of bilateral lower extremity pain, proximal weakness more pronounced than distal, as well as abdominal pain and hyponatremia of 120 mEq/L. During that admission, the patient experienced new onset seizure activity, which was erroneously attributed to polypharmacy, as well as hyponatremia. After day 15, the patient’s family requested transfer to our institution.

Upon transfer, the patient was seen by a number of specialties including, neurology, cardiology, endocrinology, gynecology, and psychiatry for evaluation. Differential diagnoses at the time included movement disorder, postural orthostatic tachycardia syndrome, menorrhagia, pheochromocytoma, and conversion disorder, respectively, all of which were ruled out. Unfortunately, the patient was again discharged home without resolution of weakness or a definitive diagnosis. The patient returned to the hospital 10 days later with complaints of chest pain, shortness of breath, and markedly increased weakness which had progressed to her upper extremities. In addition, she had developed difficulty with gait instability, dysphagia, and visual hallucinations. The patient was admitted to the Neurocritical Care unit on day 2 of admission after developing rapid, labored breathing, with use of accessory muscles. The patient continued to experience respiratory decline and required intubation on day 6.

On day 2, brain magnetic resonance imaging (MRI) with and without contrast was completed; however, no acute intracranial abnormalities were noted (Figure 2). An MRI of the cervical spine was obtained due to quadriparesis, with no identifiable intra- or extradural etiologies of her weakness. The patient also underwent a lumbar puncture on day 2 to evaluate autoimmune, metabolic and infectious etiologies, all of which were negative or within normal limits (Figure 3). Due to her deteriorating appendicular and bulbar strength, Guillain-Barré syndrome was considered and the patient was started empirically on IVIG on day 2. On day 5, nerve conduction and needle electromyography (EMG) was conducted, which showed decreased amplitude in common peroneal and median nerves with normal conduction velocities. Given the patient’s thin body habitus and lack of peripheral edema, these findings were suggestive of severe motor axonal neuropathy and determined to be consistent with porphyria. On day 3 of the patient’s hospitalization, due to continued abdominal and extremity pain, quadriparesis, hyponatremia, hallucinations, and isolated seizure activity, aminolevulinic acid (ALA) delta and porphobilinogen were sent, confirming porphyria when urine tested positive for elevated ALA. The normal range for ALA delta is 0–5.4 mg/L, therefore the patient’s initial level of 34.6 mg/L is elevated, which can be seen in Figure 4. A D10 infusion was administered at 50 mL/hr, as well as intermittent hemin infusions of 350 mg/50 mL of sterile water daily for a 2 week course. These infusions were dosed and given based on ALA delta levels to decrease the heme biosynthetic pathway. Despite completing an equivalent of a 2 week course of hemin infusions, her urine porphobilinogen remained elevated at 24.2 mg/L which is above the .0–5.4 mg/L range of normal. (Figure 4). After consultation with obstetrics and gynecology, the patient was started on medroxyprogesterone acetate injections for menstrual cycle management due to menorrhagia. Genetic testing revealed a heterozygous mutation in the Hydroxymethylbilane Synthase (HMBS) gene, specifically a c.583 C>T mutation, a missense mutation variant that is pathogenetic for AIP.

Figure 2.

Magnetic resonance imaging. (A) Cervical spine T2 sequence. (B) Thoracic spine T2 sequence. (C) Brain T2 sequence. (D) Brain FLAIR sequence. (E) Brain T2 Sequence. (F) Brain FLAIR sequence.

Figure 3.

Cerebral spinal fluid profile.

Figure 4.

Levels of aminolevulinic acid delta urine and porphobilinogen prior to and after hemin infusions.

Total ICU days equaled 45, during which the patient required a tracheostomy for prolonged intubation, a percutaneous gastric tube, and 4 red blood cell transfusions. She ultimately completed 8 infusions of hemin during her ICU stay. On day 3, the patient’s coproporphyrin I and III were 228 and 98, and on day 10, after 8 hemin infusions, they were 150 and 96, respectively. The coproporphyrin I showed greater improvement than III, though both remained above normal. The patient did show improvement of weakness in her lower extremities to a 3–4 out of 5 strength and was beginning to ambulate with assistance, with significant reduction of pain. At this point, the patient was able to transfer to inpatient rehabilitation for continued recovery, completed over a 4 week period, after which, the patient went home with full 24-hour care and outpatient physical and occupational therapy follow up. She was able to regain enough function to feed herself and use a walker. Ten weeks after the patient’s initial tracheostomy, she was decannulated. Over the next year, the patient experienced multiple readmissions for porphyria exacerbations.

Sadly, 11 months after initial ICU admission, the patient was admitted for bacteremia. She developed an acute exacerbation of her porphyria at that time coupled with sepsis. Subsequently, the patient developed septic shock from her bacteremia, resulting in acute respiratory failure, cardiac arrest, and death.

Discussion

To date, 9 types of porphyria have been identified, either acquired or inherited. Each subtype ultimately results in decreased hemin production and a buildup of heme substances. The heme pathway includes 8 precursor enzymes, most notably found in erythrocytes and hepatocytes essential to the production of hemoglobin, myoglobin, mitochondrial cytochromes, and hepatic cytochrome P450. ⁹ Genetic mutations to these enzymes disrupt the heme pathway, depleting functional heme, and accumulating toxic metabolites upstream ³ (Figure 1). Specific porphyria diagnoses are divided into either erthythropoetic or hepatic, as well as chronic or acute. Acute intermittent porphyria (AIP), an acute hepatic porphyria, is due to a genetic mutation of porphobilinogen deaminase (PBGD), the third enzyme in the pathway. Other acute hepatic porphyrias include aminolevulinic acid dehydratase deficient porphyria, hereditary coproporphyria, and variegate porphyria. ³ All acute porphyrias have only a partial enzyme deficiency, while the rest of the heme pathway usually functions normally. Due to the preserved functionality of the pathway, most patients with these mutations remain asymptomatic, with an estimation of only 10% possessing a heterozygous mutation presenting with acute attacks. ¹⁰

Porphobilinogen levels are markedly elevated in acute porphyria attacks and can be 10 to 150 times the upper limit of normal. The mainstay of treatment is hematin infusions with some patients requiring prophylactic dosing. Acutely, patients may require dosing of 3–4 mg/kg IV once daily infused over a period of 30 to 40 minutes for 4 days, with additional doses administered for worsening or recurrences. During the acute phase of AIP, patients also receive a D10 in .45% saline infusion at a rate of 300 to 500 gm/day. Glucose inhibits ALA synthase activity, and thus decreases the initial enzyme production in the heme biosynthetic pathway. ¹¹ Infusions of D10 are used until hemin infusions can be initiated. A new drug therapy involving the use of a small interfering RNA (siRNA) directed against delta aminolevulinic acid synthase 1, with the aim of reducing production of delta aminolevulinic acid, is currently being investigated. ²

Although hemin is the treatment of choice for AIP, some patients may progress even when receiving this adequate treatment. In these cases, especially in life-threatening acute attacks or disabling recurrent attacks, liver transplantation may be an option. It should be considered before the onset of long-term neurological sequelae. Some complications of liver transplantation include hemorrhage, bile leak, renal dysfunction, and hepatic artery thrombosis. ¹²

The leading pathophysiologic hypotheses of AIP is the formation of a neurotoxic environment via the combination of the depletion of heme, a key component of the mitochondrial electron transport chain, and the buildup of the neurotoxic precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). These precursors act on the central and peripheral nervous systems producing neurotoxic clinical symptoms. ⁴ Although the general pathophysiologic hypotheses of the AIP disease state is mostly understood, the exact mechanism specifically contributing to the neurotoxic nature of the toxins remains unclear. One possible explanation is the production of kidney peptide transporter 2 (PEPT2*1*) by the choroid plexus. PEPT2*1* has a strong affinity for ALA, of which there is a significant elevation in AIP. ³ The excessive accumulation of ALA in the brain is thought to contribute to depression, anxiety, seizures, and psychosis that clinically presents during an AIP flair. ³

Seizures are present in 5% of the AIT attacks and are usually complex partial and occur in the presence of hyponatremia. Another important neuropsychiatric manifestation of AIP includes motor weakness. Peripheral neuropathy, for example, can complicate acute episodes in up to 40% of the cases.^13,14 Peripheral neuropathy from AIP reaches the maximal intensity 2–4 weeks after an attack, and differentiating it from Guillain-Barré represents a challenge. Some aspects like the asymmetric proximal weakness, the presence of sensory loss, cranial nerve involvement, and the presence of deep tendon reflexes present are clues for diagnosing AIP, although they are not mandatory, and a wide range of this manifestation can occur. Also, the peripheral neuropathy from AIP is predominantly axonal, and in Guillain-Barré is usually demyelinating neuropathy. ¹³ Autonomic involvement manifestes symptoms such as vomiting, nausea, episodic sweating, tachycardia, and hypertension. Encephalopathy may present in up to 70% of acute attacks, and imaging changes can resemble Multiple sclerosis (in the form of white matter lesions) or even Posterior Reversible Encephalopathy with T2 signal areas in the occipital or frontoparietal cortices that do not enhance with contrast. Psychiatric manifestations, such as those present in this case, include anxiety and depression, delusions, anorexia nervosa causing an acute attack due to carbohydrate deprivation, and even positive or negative signs from schizophrenia.^13,15

The patient in this case was discharged twice without resolution of pain or diagnostic cause. Acute intermittent porphyria, with its vague symptomatology and rare prevalence, is often overlooked.^13,16-18 In addition to the difficulty of identifying porphyria, diagnosis in this case could have been confounded by factors of youth, gender, and culture, leading to further prolongation of the diagnostic process. While it is unclear if health disparities played a role in this case, they are imperative to identify and address, as the consequences can be devastating. ¹⁹

Early detection and treatment are vital to ensuring independence and quality of life. The triad of intermittent seizures, abdominal pain, and hyponatremia in a young woman should raise clinical suspicion for porphyria. Improved diagnosis should occur as we become more familiar with symptoms, root cause, and treatment options for AIP. Hopefully, preventing severe manifestations of the disease, leads to quicker recovery, with longer chronic maintenance periods.

ORCID iDs

Shannon Burns https://orcid.org/0000-0002-9173-088X

Gabriela Figueiredo Pucci https://orcid.org/0000-0002-6597-6106