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Despite effective prophylactic and acute treatments for acute hepatic porphyria, many patients face a long, painful path to diagnosis.

Not only is the condition underdiagnosed, but the delay in time to diagnosis stretches more than a decade for some patients, noted Manisha Balwani, MD, interim chief of medical genetics and genomics at the Icahn School of Medicine at Mount Sinai in New York City.

This rare genetic metabolic disorder, characterized by accumulation of porphyrin heme precursors due to enzyme deficiency in the liver, most often strikes women in their reproductive years. While there are a variety of genetic mutations that cause porphyrias, acute hepatic porphyrias can be by drugs interacting with the liver enzymes involved in heme synthesis.

"Not all with a pathogenic variant in the gene will develop attacks," Balwani noted. "The majority of patients will not develop symptoms."

A documented a population rate of 5 to 10 per 100,000 individuals developing acute intermittent porphyrias overall, whereas the prevalence of genetic mutations that lead to them was approximately one in 1,675.

The most typical symptoms of an acute hepatic porphyria attack are fairly nonspecific: abdominal pain, chest and back pain, nausea, vomiting, constipation, and tachycardia. Seizures, peripheral neuropathy, and severe muscle weakness, even leading to respiratory failure, can also occur. For such attacks, IV hematin (Panhematin) treatment in the hospital helps resolve acute symptoms.

However, many patients have recurrent attacks of acute hepatic porphyria and develop chronic symptoms, such as pain, nausea, and fatigue.

"For some of these patients the pain is daily and they need active pain management," Balwani noted. "The pain they experience is extreme. So if you ask a patient with acute hepatic porphyria 'On a scale of zero to 10 how bad is your pain?' Most say it's an 11. ... Tremendous disability, which I don't think is recognized in this subset of patients."

The long delay in diagnosis that can lead to appropriate management is in part because of the multitude of specialties to which these patients might present, she suggested.

"Because they can present with very nonspecific symptoms, these patients can go really anywhere," with many healthcare visits to internal medicine, gastroenterology, ob/gyn, and other specialties, and frequently ending up in the emergency department, she said.

"And because this is a disorder which is not at the top of a differential when you think of abdominal pain, nausea and vomiting, these patients usually have an extensive workup for GI [gastrointestinal] issues," she added. "In young women, some of the most common misdiagnoses we see are urinary tract infection (because they have dark colored urine during acute attacks) or appendicitis, cholelithiasis, or pancreatitis or gastrointestinal mobility disorder, ovarian cysts -- you name it."

For physicians unsure of how to make the diagnosis in these rare patients and then treat them, Balwani offered tips.

Much of the older literature recommends a 24-hour urine test, but that test is not specific for porphyria. Testing for urine porphyrin commonly shows slight elevations that "lead to a lot of confusion and misdiagnosis," Balwani noted. The best strategy is to simply run a porphobilinogen (PBG) test on a spot sample of urine, she said.

If the PBG is elevated, the next step is genetic testing to determine the type of porphyria. Multigene panels can be run for porphyria, some of which are free to patients, Balwani noted.

However, not all labs do these tests well, she cautioned. "You want to choose the right lab to do it. These samples should be corrected to urine creatinine."

Physicians can find expert centers and laboratories through the NIH-supported and the .

"It's always beneficial to have patients consult at an expert center so they can get the right information, particularly with a new drug and new developments," Balwani said, referring to the prophylactic treatment drug givosiran approved in late 2019 on priority review and orphan product and breakthrough therapy designations from the FDA.

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