Acute intermittent porphyria.

To the Editor,

Acute intermittent porphyria is one of the group of diseases involving hereditary defects in heme synthesis and results in excessive secretion of porphyrins and porphyrin precursors. It is characterized by a spectrum of signs and symptoms varying from abdominal pain, neuropathies and mental disturbances that are often precipitated by drugs and other factors.[1]

A 19-year-old male presented to the emergency department with complaints of abdominal pain, bilious vomiting and constipation for the past 5 days. This was not associated with fever or jaundice, and the patient was not on any medication as per available history. Examination of the various systems was unremarkable including that of the abdomen. Patient's pulse rate was 118/min and blood pressure was 158/94 mmHg. A clinical diagnosis of subacute intestinal obstruction was made, which was substantiated by abdominal X-ray finding of dilated bowel loops. Patient was managed conservatively with intravenous (I/V) fluids, analgesics, antiemetics and antibiotics. Investigations including serum electrolytes were within normal range.

However, the pain aggravated 36 h after admission and therefore the patient was taken up for exploratory laparotomy that, however, did not reveal anything significant except mesenteric lymphadenopathy. General anesthesia was given, which included the fentanyl, propofol, atracurium, paracetamol, diclofenac sodium, isoflurane, nitrous oxide and ondansetron in standard doses and routes. Neuromuscular blockade was reversed with neostigmine and glycopyrrolate. An uneventful perioperative period was followed by an episode of generalized tonic clonic seizure 24 h later. The serum sodium level was found to be 117 meq/L. So, sodium correction was started as per the standard formula Na+ deficit = total body water (desired Na+ — present Na+).[2] By this time, the patient had suffered three more seizure episodes, which were controlled with injection midazolam 2 mg I/V slow, but his consciousness deteriorated to a Glasgow Coma Scale of 3/15. Patient was intubated and put on ventilatory support in the intensive care unit (ICU) under titrated midazolam and fentanyl sedation.

After 4 h, it was found that even with a standard formula the sodium rose at a rate of 3 meq/h, which is double than what is recommended.[2] Hence, the rate of infusion was halved, and hourly monitoring was done. The patient's consciousness did not improve despite normalization of sodium levels, hence a magnetic resonance imaging (MRI) brain was performed, which revealed bilateral and symmetrical parieto-occipital edema going in favor of posterior reversible encephalopathy syndrome (PRES).

On probing, the attendants (mother came later) revealed that the patient had suffered a similar episode of abdominal pain 2 years back, which was managed conservatively. The constellation of neurological symptoms with abdominal pain led to a suspicion of porphyria, so urine examination for porphobilinogen was conducted, which was positive, thereby confirming a diagnosis of acute intermittent porphyria. The patient's neurological condition remained same and patient deteriorated hemodynamically after around 45 days of ICU care and was put on inotropes. The patient had a cardiac arrest after 56 days of ICU care on a ventilator and could not be revived.

Acute intermittent porphyria may present with neurovisceral and psychiatric disturbances like abdominal pain, constipation, insomnia, depression, disorientation and hallucinations.[1] The porphyrias are classified as either hepatic or erythropoietic, depending on the primary site of overproduction and accumulation of their respective porphyrin precursors or porphyrins, although some have overlapping features. The major manifestations of the acute hepatic porphyrias are as described above while the erythropoietic porphyrias usually present with cutaneous photosensitivity at birth or in early childhood.[1]

Our patient came with main complaints of abdominal pain, which is a presenting symptom in approximately 85% of cases.[3] This is due to autonomic neuropathy and is associated with vomiting and constipation in nearly 50% of cases.[3] Thus, our patient came with the commonest presentation of the rare disease of porphyria, but with no other history coming from the attendants (as the patient was brought to the hospital by acquaintances) and the presence of dilated bowel loops in the X-ray led to the possible diagnosis of subacute intestinal obstruction, which in our setup is largely caused due to tuberculosis. Paralytic ileus is also a manifestation due to autonomic dysfunction in porphyria.[4]

Following aggravation of symptoms, the patient was inadvertently exposed to a negative laparotomy, which, unfortunately, happens in many porphyria cases.[56] The drugs used during surgery were incidentally safe for patients of porphyria.[7]

Seizure episodes in porphyria can occur in 2-20% of acute attacks.[3] These can be a sign of porphyria induced encephalopathy or hyponatremia, which is due syndrome of inappropriate antidiuretic hormone secretion[5] but can also occur due to damage to the supraoptic nuclei of the hypothalamus or due to nephrotoxicity.[8] The serum sodium level was found to be very low in our case, hence the correction according to the standard formula[2] was started.

The curious case of this patient was that rate of rise of serum sodium was far higher than what happens in other patients though there was no deviation from the rate of infusion according to correct formula. The same has been reported earlier in the literature and without any sequelae.[9] The multitude of factors involved in these cases along with dysautonomia and sympathetic overactivity may lead to abnormal responses to treatment.

Posterior reversible encephalopathy syndrome is one of the findings in porphyria with neurological manifestations.[3] MRI findings in these cases suggest that the blood brain barrier in these cases is breached, which allows neurotoxins like aminolevulinic acid to reach and damage the neurons.[310] In the first instance, the cause of the seizure was directed toward hyponatremia but retrospectively, after MRI reporting, the cause of same can be either or a combination of both the causes.

Though PRES is described as a reversible clinico-radiological diagnosis in several cases, it is related to poor prognosis leading to death, with a fatality rate reported up to 15%.[10]

A history of a similar past episode, along with negative laparotomy, hyponatremia and neurological features led to the presumptive diagnosis of acute intermittent porphyria, which was confirmed by high levels of porphobilinogen in the urine sample.

The patient was given high carbohydrate infusions and then through nasogastric tube when ileus improved (400 g/day), which has been shown to improve the outcome in acute attacks. Haem arginate, which is the only other treatment modality was not available.

Our patient remained hemodynamically stable since the onset of the attack and even after prolonged ventilation, which may be due to sympathetic overactivity in these cases.[5]

The patient deteriorated after 45 days of ICU care and had cardiac arrest. The fatal outcome of porphyria is a rare incidence and is related PRES or neurological symptoms like seizures, cerebral ataxia, loss of consciousness, etc. Other features like peripheral neuropathy, muscle weakness, bulbar palsies, need for mechanical ventilation and severe hyponatremia have been implicated as markers of poor outcome.[3]

Thus, a patient presenting with acute abdominal pain with electrolyte imbalance and/or with any peripheral or central neurological symptoms should remind us of this rare disease and should be kept as an important differential diagnosis. Moreover, we require institution of and strict adherence of drug protocols. By classifying drugs into categories of definitely, likely and probably pophyrogenic, these patients can be better managed. Such lists are already in use in several European nations, but better drug protocols are needed in our country as well.