Acute Hepatic Porphyrias: Review and Recent Progress

Abstract

The acute hepatic porphyrias (AHPs) are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms. The four types are 5‐aminolevulinic acid (ALA) dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Their diagnoses are often missed or delayed because the clinical symptoms mimic other more common disorders. Recent results indicate that acute intermittent porphyria, the most severe of the more common types of AHP, is more prevalent than previously thought, occurring in about 1 in 1600 Caucasians, but with low clinical penetrance (approximately 2%‐3%). Here we provide an updated review of relevant literature and discuss recent and emerging advances in treatment of these disorders. Symptomatic attacks occur primarily in females between 14 and 45 years of age. AHP is diagnosed by finding significantly elevated levels of porphyrin precursors ALA and porphobilinogen in urine. Acute attacks should be treated promptly with intravenous heme therapy to avoid the development of potentially irreversible neurologic sequelae. All patients should be counseled about avoiding potential triggers for acute attacks and monitored regularly for the development of long‐term complications. Their first‐degree relatives should undergo targeted gene testing. Patients who suffer recurrent acute attacks can be particularly challenging to manage. Approximately 20% of patients with recurrent symptoms develop chronic and ongoing pain and other symptoms. We discuss newer treatment options in development, including small interfering RNA, to down‐regulate ALA synthase‐1 and/or wild‐type messenger RNA of defective genes delivered selectively to hepatocytes for these patients. We expect that the newer treatments will diminish and perhaps obviate the need for liver transplantation as treatment of these inborn metabolic disorders.

Therapeutic strategies for acute intermittent porphyria

“…Mild attacks should initially be treated with oral glucose, but patients who are not tolerating oral glucose can be given glucose intravenously (300-500 g/day, preferably 10% dextrose in 0.45% saline) as a preferred source of energy (16,23), in order to down-regulate the activity of ALAS1 and prevent fasting (24). Moreover, the combination of glucose with insulin can be more effective because insulin can also hamper ALA synthesis induced by PGC1-α (25).…”

“…In addition, patients should give up smoking and limit alcohol. Generally, no more than two drinks a day for men and no more than one for women are recommended (16).…”

“…Progesterone is a porphyrin inductor and an effective inducer of ALAS1 (78,81). Therefore, women with recurrent premenstrual attacks of AIP can be given GnRH analogues (leuprolide or histrelin) to prevent ovulation and alleviate symptoms (16). GnRH treatment is initiated during the first 1-3 days of a menstrual cycle to reduce the risk of an AIP attack precipitated by transient ovarian stimulation (15).…”

“…Annual examination of creatinine and eGFR are also recommended for all patients. In addition, patients with AIP should refrain from using nephrotoxic drugs and drink more water (16). The angiotensin-converting enzyme inhibitor losartan may delay the development of renal impairment (10,102).…”

“…If the patient has already developed renal impairment, blood purification or kidney transplantation is often helpful. For patients with AIP and kidney failure, renal transplantation or combined liver-kidney transplantation can have a good curative effect (16,102). Liver impairment is common in patients with AIP.…”