Pathophysiology, Pharmacology and Treatment of Acute Intermittent Porphyria: A Patient Case Description and Recommendations from the Current Literature

Abstract

Acute intermittent porphyria (AIP) is a rare and potentially life-threatening metabolic disorder. It is characterized by an autosomal dominant enzymatic deficiency in porphobilinogen deaminase, which is a critical enzyme in the heme biosynthesis pathway. This deficiency leads to an overproduction of porphyrin precursors that can lead to acute attacks that can be severe and affect overall quality of life. These attacks can be precipitated by factors such as medications, nutritional changes, infection and environmental exposures. Liver transplantation is a potential cure for patients who have evidence of end-stage liver disease or are experience multiple life-threatening attacks. This article presents the case of a patient with AIP, who was successfully treated with liver transplantation. The article also provides a review of the epidemiology/pathophysiology of AIP, and its diagnosis and precipitating factors leading to exacerbation of symptoms, as well as its treatment options, with an emphasis on use of liver transplantation to achieve cure.Keywords: Acute intermittent porphyria; Liver transplant; Panhematin; Hemin. Abbreviations: AIP, Acute intermittent porphyria; OLT, orthotopic liver transplantation; PBGD, porphobilinogen deaminase; PBG, porphobilinogen; ALA, aminolevulinic acid; ALAS, 5-aminolevulinic acid synthase; CEP, congenital erythropoietic porphyria; HCP, hereditary coproporphyria; HEP, hepatoerythropoietic porphyria; HMB, hydroxymethylbilane; PBG, porphobilinogen; PCT, porphyria cutanea tarda; VP, variegate porphyria; CYP 450, cytochrome P450; HAT, hepatic artery thrombosis. Case presentationA 30-year-old female diagnosed with acute intermittent porphyria (AIP) at age 16 presented to our transplant center for consideration of orthotopic liver transplantation (OLT). She had the c517C > T exon T mutation in the porphobilinogen deaminase (PBGD) gene. During the first 2 years after her diagnosis she had several hospital admissions Due to her disease. She was subsequently treated with weekly hematin infusions and bimonthly phlebotomies to manage the resultant hyperferritinemia from her constant heme infusions. She reported a poor quality of life due to abdominal pain resulting in multiple hospital admissions. She also experienced significant fatigue and lethargy for several days following her hematin infusions. She described an average of 1-2 days of acceptable energy before experiencing symptoms again. Concern for her overall health and poor quality of life prompted her interest in liver transplantation as a cure for her disease. She felt that the risks of transplant and a lifetime of immunosuppression outweighed the risk of end organ damage and poor quality of life from her AIP.The patient was evaluated for a liver transplant during a phase in her management marked by clinical stability. Prior to transplant, her urinary porphobilinogen (PBG) excretion was 269.7 mcmol/L, consistent with the diagnosis of AIP. She also had a serum ferritin level of 327 ng/mL, iron of 23 mcg/dL, and percent iron sa...

<p>Acute Intermittent Porphyria: Current Perspectives And Case Presentation</p>

“…Poor nutritional states can induce an acute episode as well 14. The mechanism of action occurs via the enzyme heme oxygenase-1 which both decreases hepatic heme production and induces ALAS synthesis leading to increased PBG and ALA production.…”

“…Some theorize that excess PBG and ALA causes the syndrome of inappropriate antidiuretic hormone (SIADH) via neurotoxigenic mechanisms. Psychiatric symptoms may occur both during acute episodes or become chronic diagnoses in the form of depression, anxiety, hallucinations, psychosis, or delirium 14…”

“…Porphyrins are excreted in the urine and stool. However porphyrin fecal studies in AIP are routinely normal while they are elevated in hereditary coproporphyria and variegate porphyria 14. As such, urine and stool specimens are integral to establishing the diagnosis (Table 3).…”

“…During an acute attack, PBG levels in the range of 20–200 mg/L are diagnostic. Following remission, PBG levels can remain elevated between 10–20 mg/L 14. ALA levels are not necessary to establish the diagnosis.…”

“…It is important to recognize these offending medications and discontinue them if thought to be contributing to an acute flare 18. If patients have uncontrolled disease despite therapy or experience significant side effects from the aforementioned interventions, then liver transplantation has been shown as definitive treatment 14…”