Case Presentation: A 77-year-old woman of German descent with past medical history of breast cancer, factor V leiden, pulmonary embolism, deep vein thrombosis, atrial fibrillation and fibromyalgia who presented after recurrent hospitalizations with complaints of debilitating fatigue, bilateral lower extremity weakness, abdominal pain and nausea. During this hospitalization, she also complained of passage of dark urine. She denied any recent medication changes or stressors, cigarette smoking or alcohol use. She reported a positive family history of pancreatic cancer in her father and paternal uncles. Complete blood count, comprehensive metabolic panel and complete rheumatologic panel were normal. Myoglobin was < 26 ng/mL, creatine kinase was 44 U/L. Electromyography and nerve conduction study of lower extremities revealed mild sensory axonal neuropathy. Work up for suspected AIP revealed elevated urine porphobilinogen of 108.7 mg/g of creatinine, serum coproporphyrin of 334.6 mcg/g of creatinine, total porphyrins of 507.5 mcg/g of creatinine and slightly elevated uroporphyrins. Genetic panel revealed positive hydroxymethylbilane synthase (HMBS) gene mutation. Patient was started on dextrose infusion with improvement of symptoms, discharged on glucose tablets to manage acute attacks, with plans to initiate Givosiran in the clinic.
Discussion: Porphyrias are defects in heme synthesis caused by alterations in one of the eight enzymes of heme biosynthesis. Acute intermittent porphyria (AIP) is an acute hepatic porphyria caused by a partial deficiency of the porphobilinogen deaminase (PBGD) enzyme. It is an autosomal dominant disorder which is more common in people of Northern European descent, a disease with low penetrance (as low as 1%) occurring in about 50 per million of the population. The liver drives overproduction of heme pathway intermediates in patients with AIP, these substrates are neurotoxic. Symptoms can be triggered by metabolic stress, sex hormones, certain medications, caloric and carbohydrate restriction. Porphobilin and porphyrins are elevated in AIP accounting for the reddish-brown urine discoloration seen in acute attacks. AIP can be managed by avoidance of triggers; treatment options include oral/IV glucose or IV hemin at 3-4 mg/kg/day for 3 to 14 days. Givosiran is an ALAS1 inhibitor that can be given subcutaneously once a month for prevention of frequently recurring attacks. Genetic screening of family members is recommended.
Conclusions: Although it is rare and challenging to diagnose, AIP has a significant morbidity including debilitating effects of weakness, pain, fatigue and potential mortality with involvement of respiratory muscles; for these reasons, a high index of suspicion should be maintained in patients with vague neurovisceral symptoms.