Challenges in the successful management of a case of acute intermittent porphyria in India

Introduction

Acute intermittent porphyria (AIP) is a part of a group of disorders involved in defective haem biosynthesis resulting in accumulation and excessive secretion of porphyrins and its precursors. AIP is the second most common porphyria preceded only by porphyria cutanea tarda. ¹ Porphyrias present with acute episodes of severe abdominal pain, nausea, confusion and severe life-threatening seizures. ¹ A high index of suspicion is required for the initial diagnosis of AIP. We present the case of a young man who presented with AIP, successfully treated with human haematin.

Case report

An 18-year-old man presented with generalised abdominal pain, fever, generalised tonic-clonic convulsions and rapidly progressing bilateral symmetric weakness of all four limbs without ocular, bladder or bowel involvement. His illness had started 4 months previously. One week before admission his relatives reported a gradual deterioration of consciousness together with laboured respiration. A sibling with a similar history had died the year before without a definite diagnosis having been made.

The patient had been admitted several times at various hospitals but despite multiple evaluations including repeated endoscopies, an ultrasound and computed tomography (CT) scan of the abdomen, no definite cause of his abdominal pain had been identified. For his neurological complaints an extensive workup including a haematological profile, blood and cerebrospinal fluid cultures, and a magnetic resonance imaging (MRI) scan of the brain (which showed bilateral basal ganglia hyper-intensity on T2-weighted images and fluid attenuated inversion recovery with possibility of metabolic deposit/encephalopathy) (Figure 2) had not pointed to any specific aetiology.

Upon presentation, the patient was in respiratory distress. He was unconscious and did not respond to deep pain stimulation but had reactive pupils. He had generalised hypotonia and areflexia. Examination of other systems, including the abdomen and skin, was not contributory. He was thus admitted to intensive care, intubated and mechanical ventilation was instituted.

The urine was found to be pinkish and it further darkened on exposure to light (Figure 1), however no blood or red cells were detected. A qualitative screening test for porphobilinogen (PBG) was strongly positive. This was confirmed by a 24-h quantitative test (28 mg/24, normal <3.4 mg/24 h). Acute poprhyria most likely acute intermittent porphyria, was diagnosed. Confirmation of the diagnosis requires enzymatic assay levels and genetic tests, which are not available in India. A nerve conduction study, however, showed bilateral symmetrical motor neuropathy of all four limbs.

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Figure 1.

Pink urine darkened to deep red on exposure to light.

The patient was treated intravenously with Haem Arginate (Normosang™, Orphan Europe), 3 mg/kg/day for 4 days. After 2 weeks of intensive care, he was weaned off the ventilator and transferred to a general ward. An MRI brain at this juncture revealed focal, symmetrical non enhancing signal abnormalities bilaterally including cystic changes in the internal capsule, external capsule and sub cortical white matter (Figure 2). He made slow progress and over the course of the next 2 months made an almost complete neurological recovery.

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Figure 2.

T2-weighted axial sections on MRI reveals focal symmetrical abnormal non-enhancing signal abnormalities involving bilateral capsuloganglionic, temporal, frontal lobe, basal ganglia and thalami as well as internal capsule, external capsule and subcortical white matter on both sides.

Discussion

A majority of acute attacks of porphyria present with abdominal pain, dysautonomia and central nervous system (CNS) symptoms. CNS manifestations include seizures, neuropathic pain, encephalopathy and global hyporeflexia. ² MRI changes usually include symmetric and reversible involvement of the cortical and subcortical areas of the occipital and parietal lobes. These changes are consistent with an evolving ischaemic injury due to vasogenic oedema and transient breakdown of the blood–brain barrier.^2,3

The urinary PBG test is the best initial test for the diagnosis of AIP and other porphyrias, namely hereditary coproporphyria (HCP) and variegate porphyria (VP). A screening test is normally followed by a 24-h urine sample, collected for quantitative measurement of amino laevulinic acid (ALA), PBG and total porphyrins. ⁴ As the acute porphyrias are treated on similar lines, once there is a definite laboratory documentation of a substantial increase in urinary or plasma PBG, treatment can be started while further testing is in progress. The biochemical and genomic tests for definite diagnosis are not widely available.

Although difficult to procure, human haematin is the drug of choice in AIP.^5,6 It reduces the overproduction of aminolaevulinic acid which causes the symptoms of AIP, including encephalopathy and neuropathy. As only two companies in the world manufacture it, we made direct contact with a manufacturer in France. Besides raising the requisite sum (approximately INR 200,000), special permission had to be sought from the Customs and the Central Drugs Standard Control Organization on an urgent basis to import this medication. Early initiation of treatment is the only way to prevent long-term neuropathy in AIP patients. ⁷

Although it may be very difficult to obtain, Haem Arginate gives excellent results. The dramatic recovery with complete reversal of encephalopathy and neuropathy seen in our patient justifies the herculean efforts to overcome financial and bureaucratic hurdles in obtaining this essential medication.