Not So Benign
Acute Hepatic Porphyria: Rare, Potentially Devastating Disorders of Heme Biosynthesis Free

Apart from ALAD (which is autosomal recessive and ultra rare), AHPs are inherited in an autosomal dominant manner with incomplete penetrance.^3-5  In AIP, penetrance is less than 10%,^3,4  although this may vary depending on the specific pathogenic variant present.⁵  The vast majority (80-90%) of symptomatic patients are women of reproductive age, with symptoms rarely occurring before puberty.^4,6  Affected patients present with neurovisceral symptoms including acute abdominal pain (74%), nausea/vomiting (73%), and weakness (63%).⁶  Patients with HCP and VP may also develop cutaneous manifestations such as blistering and scarring on sun-exposed areas.¹  Central nervous system involvement can cause agitation, hallucinations, seizures, and hyponatremia, while sympathetic nervous system manifestations include fever, tachycardia, hypertension, and diaphoresis.⁴  In severe attacks, respiratory weakness can lead to respiratory failure, need for mechanical ventilation, or even death.⁴ 

In one U.S. cohort of 108 patients, diagnosis was delayed by a mean of 15 years.⁶  While most affected patients experience long periods of quiescence punctuated by acute attacks, about 20% develop chronic symptoms, in particular neuropathic pain, which can be debilitating and greatly impair quality of life.^5-7  Patients with AHP also report feelings of isolation due to living with a rare disease, as well as concern that health care providers will dismiss the severity of their pain or not know how to treat their disease appropriately.⁷ 

The initial diagnosis of AHP is made by biochemical testing, with a low threshold to screen patients with unexplained abdominal pain or neurologic symptoms. The initial diagnostic test for AHP includes a spot urine PBG and ALA, normalized to creatinine.⁸  During acute symptoms, significant elevations in urine PBG are highly specific for AHP, with levels often greater than 10 times the upper limit of normal.^3,4  In patients with VP and HCP, plasma porphyrins may also be elevated, especially if cutaneous symptoms are present. Testing should be performed as close to symptom onset as possible, as levels of porphyrins and porphyrin precursors may return to normal between attacks.⁴  Normal levels of urine PBG and ALA collected and handled appropriately during or soon after a symptomatic episode exclude AHP as a cause of the symptoms.^3,4 

Once a biochemical diagnosis of AHP has been made, next-line testing may include evaluation of urine and fecal porphyrins, plasma porphyrins, plasma fluorescence scan, and hydroxymethylbilane synthase enzyme activity. For instance, fecal porphyrins are often elevated in patients with HCP and VP,⁸  and patients with VP have a characteristic plasma fluorescent peak at 626 nm. Genetic testing is the “gold standard” for confirmation and characterization of the type of porphyria, and it is recommended in patients with a confirmed biochemical diagnosis for the purposes of screening first-degree relatives and counseling. However, genetic testing is not recommended as a first-line diagnostic test. The low penetrance of AHP means that most patients with pathogenic gene variants will not develop clinical disease, and identification of a variant could lead to misattribution of non-specific symptoms.^3,4 

Principles of acute management are as follows:^3,4 

1. Identification and removal of triggers. Important modifiable triggers include medications, alcohol use, fasting (especially low-carbohydrate diets), and physiologic stress (e.g., surgery, infections). Drug safety can be verified using a reputable drug database, such as the Norwegian Porphyria Center’s acute porphyria drug database: drugs-porphyria.org.

2. Symptomatic management, including pain control, antiemetics, management of autonomic dysfunction, and monitoring for hyponatremia.

3. Intravenous glucose, aiming for at least 300 g per day. This can be accomplished through administration of a solution of 10% dextrose mixed one to one with 0.9% sodium chloride at 120 to 150 cc per hour.

4. Hemin infusion (Panhematin^® in the U.S. and Canada) is the standard of care for acute attacks. Hemin infusion takes advantage of the negative feedback of heme on ALAS1 expression in the liver, reducing ALA and PBG production. The dose is 3 to 4 mg/kg per day, typically for four days. Hemin should be reconstituted with albumin to prevent complications such as superficial thrombophlebitis. With repeated administrations, hemin may lead to iron overload.

Most affected patients experience infrequent attacks (sometimes only a few in a lifetime). However, up to 8% of patients can experience frequent, repeated acute attacks and should be considered for prophylactic treatment.⁴  Historically, intermittent hemin infusions have been used for this purpose, though this strategy is inconvenient and does not fully mitigate symptoms in many patients.^3,4  In some female patients with catamenial attacks, gonadotropin-releasing hormone agonists may be effective.⁹ 

In 2019, the U.S. Food and Drug Administration approved givosiran, a targeted RNA interference (RNAi) therapy that leads to degradation of hepatic ALAS1 messenger RNA, for prophylaxis in AHP.^2,10  The phase III randomized, double-blind, placebo-controlled ENVISION trial demonstrated a 74% reduction in the mean annualized attack rate in patients treated with givosiran, as well as lower levels of urinary ALA and PBG.¹¹  Givosiran is administered as a monthly subcutaneous injection and is generally well-tolerated, with side effects including fatigue, nausea, injection-site reactions, and mild increases in alanine aminotransferase (ALT) and creatinine.^2,10  ALT and creatinine elevations typically resolve with continued treatment though sometimes require an interruption in therapy.¹⁰  Elevations in homocysteine have also been observed in some patients treated with givosiran and typically resolve with vitamin B6 supplementation.^2,10 

All patients with AHP should be monitored for long-term complications such as renal dysfunction, liver disease, hepatocellular carcinoma, neuropathy, and chronic pain.³  Liver transplantation is the only known cure for AHP, but given the inherent risks associated with this procedure and the availability of effective pharmacotherapies, it is now only recommended for refractory patients with intractable symptoms.³ 

The AHPs are rare, potentially devastating disorders of heme biosynthesis. Diagnosis can be challenging given the non-specific nature of symptoms and lack of familiarity with appropriate biochemical testing among many health care providers. However, the importance of prompt and accurate diagnosis is critical, especially with the availability of highly effective therapies for both acute attacks and attack prevention. All consultative hematologists should be familiar with the fundamentals of the diagnosis and management of AHP.

Dr. Scott has received meeting travel support and honoraria from Alnylam Pharmaceuticals and Recordati Rare Diseases. Dr. Leaf has served as a consultant for Alnylam Pharmaceuticals and Recordati Rare Diseases and receives grant funding from Disc Medicine.