Acute Intermittent Porphyria

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: HMBS (HGNC:4982)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 09/07/2023
• Curation Status: Released (2.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
HMBS	acute intermittent porphyria (0008294)	176000	Strong Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric. Further evidence is needed regarding the penetrance of pathogenic variants within an unselected population.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from acute neurovisceral attacks / Evaluation and management by specialists, including hemin administration, avoidance of triggers, and patient education	2	2D	3B	3	10DB
Morbidity and mortality from hepatocellular carcinoma (HCC) / Evaluation and surveillance by specialists for early detection of HCC	2	1A	2B	3	8AB

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence estimates for individuals with symptoms of acute intermittent porphyria (AIP) range from 1/75,000 to 1/132,000.

Clinical Features (Signs / symptoms)

The acute hepatic porphyrias (AHP) are rare inborn errors of heme-metabolism and include four subtypes, with the most common and most severe being AIP. AIP is characterized by intermittent and sometimes life-threatening acute neurovisceral attacks of severe pain, usually abdominal and generalized, without peritoneal signs. While all individuals with a pathogenic variant in HMBS are predisposed to acute attacks, most never have symptoms, and are said to have latent (or presymptomatic AIP). Attacks may be accompanied by nausea, vomiting, distention, constipation, diarrhea and ileus. Tachycardia, hypertension, and hyponatremia can occur, with fever, sweating, restlessness, and tremor occurring less frequently. Urinary retention, incontinence, and dysuria may be present. Neurologic findings may also occur including mental changes (e.g., insomnia, paranoia), convulsions, hallucinations, peripheral neuropathy (that may progress to respiratory paralysis), pain in extremities, paresis, weakness, and altered consciousness (from somnolence to coma). Seizures may occur in acute attacks, especially in individuals with hyponatremia. Attacks may be provoked by certain drugs, crash dieting, alcoholic beverages, smoking, endocrine factors, calorie restriction, stress, and infections or surgery which can increase the demand for hepatic heme. Attacks are usually due to the additive effects of several triggers, including some that are unknown. Individuals are usually well between attacks.

Natural History (Important subgroups & survival / recovery)

The risk that an individual with latent AIP will later develop symptoms depends on age, sex, exposure to provoking agents, and other factors. In the majority of cases, no attacks of AIP occur during all adult life and the disease is rarely progressive. Attacks rarely occur before puberty, usually beginning in the third or fourth decade of life. Attacks are more common in females than males, with acute attacks in females often related to the menstrual cycle; however, in one study the risk difference between female and male individuals disappeared when stratified for urine porphobilinogen (PBG) levels. Most symptomatic individuals with AIP have one or a few attacks in their lifetimes. Approximately 3-8% of symptomatic individuals (mainly females) have recurrent attacks (defined as >3 per year) that may persist for years. Affected individuals may recover from acute attacks within days, but severe attacks that are not promptly treated may take weeks or months to recover from. Long term complications can include chronic renal failure (in approximately 70% of individuals with recurrent attacks), hepatocellular carcinoma (HCC), and hypertension. Individuals with AIP, whether symptomatic or latent, appear to be at increased risk of developing HCC, usually after age 50 years. Some patients experience chronic neuropathic pain, which may account for an increased risk for depression and suicide. Pregnancy is usually well-tolerated, but it increases attacks in some women. Mortality directly related to acute attacks is now very rare in most countries as a result of improved treatment. However, sudden death, presumably from cardiac arrhythmia, may occur during an acute attack. Death may also occur as a complication of HCC or liver transplantation. Liver transplantation is curative and reserved for people with intractable symptoms who have failed other treatment options.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

1-2 in 1000

The prevalence of pathogenic variants in HMBS is estimated to be 1/650-1/1785. (Tier 3)

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

5-39 %

Penetrance for individuals with HMBS pathogenic variants is estimated to be 22.9% in families with AIP and 12.7% in the relatives of the proband.

Tier 3

5-39 %

Approximately 80% of individuals with a pathogenic variant remain asymptomatic and others may have only 1 or a few acute attacks throughout life.

Tier 2

5-39 %

Using Finnish porphyria registry data, penetrance was calculated in 14 families with that had > 9 individuals with AIP per family. Mean penetrance for all acute symptoms was 35%. The penetrance was higher among female (50%) than male patients (17%). Penetrance for hospitalized attacks was 30% among AIP families (range 10–80%, for women 41%) demonstrating wide variations among families even with the similar genotype.

Tier 5

Unknown

Approximately 90% of patients with symptomatic AHP are women and attacks are rare before onset of menses or after menopause in these patients. Among symptomatic patients with AHP, >90% experience only 1 or a few acute attacks in their lifetimes. An estimated 3%–5% of patients with symptomatic AHP experience frequent recurrent attacks, typically defined as 4 or more attacks per year. In addition to the acute attack symptoms described, >50% of patients who experience recurrent attacks report chronic neurologic symptoms, and 35% have received a diagnosis of neuropathy.

Tier 3

1-4 %

A systematic review of the incidence of HCC in individuals with porphyria included 7381 patients from 19 studies. However, details on the subtype of porphyria were not consistently reported across studies. Primary liver cancer was diagnosed in 351/7381 patients (4.8%), of whom 243 (3.3%) were found to have HCC.

Tier 1

1-4 %

Using data from a Swedish porphyria registry with 1063 individuals with AIP, annual primary liver cancer (PLC) incidence of 1.7%–2.1% was found in patients aged over 50 years who had a history of clinically (hospitalizations) or biochemically (elevated urine PBG) active disease. No association with AIP genotype or sex was associated with increased risk of PLC.

Tier 3

5-39 %

In the longitudinal study of the US Porphyrias Consortium, which enrolled symptomatic, asymptomatic, and latent AHP patients, chronic kidney disease and hypertension were reported in 29% and 43% of patients with AIP (n=90), respectively.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on relative risk was identified.

Expressivity

The course of acute attacks is highly variable within and between individuals.

Tier 4

Intervention Effectiveness

Patient Management

To establish the extent of disease and needs in an individual diagnosed with latent AIP the following evaluations are recommended:

• Full clinical history and examination, including neurologic evaluation

• Quantitation of urine PBG excretion to establish a baseline for comparison with future measurements taken during symptoms suggestive of active porphyria

• Referral to a porphyria specialist for more detailed clinical advice on AIP

• Consultation with a clinical geneticist and/or genetic counselor

Tier 4

All medications given to an individual with AIP should be checked for their safety.

Tier 2

Acute attacks of AIP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein. Due to the lack of available rapid 5-aminolevulinic acid (ALA) or PBG tests, initiation of hemin can be made on empirical grounds in individuals with confirmed AIP. Timely initiation of hemin therapy results in normalization of ALA and PBG levels, symptom improvement, and decreased risk of long-term neurologic complications. Many uncontrolled clinical studies suggest a favorable biochemical and clinical response to hemin. In general, early initiation of intravenous hemin is associated with improved outcome, and hemin is more effective than glucose in reducing excretion of porphyrin precursors. The only placebo-controlled trial of hemin involved 12 patients with AIP, and found striking decreases in urine PBG excretion and trends in clinical benefit (less pain, decreased need for pain medication, and shorter hospital stay); however, the study lacked statistical power to identify a significant difference. In a larger, uncontrolled study of 22 patients (mean age at time of attacks was 37.5 years; range 21 to 67 years) with 51 acute attacks treated with hemin, treatment was initiated within 24 hours of admission in 37 attacks (73%). All patients responded (including 2 patients with paresis), and hospitalization was less than 7 days in 90% of cases.

Tier 2

An open-label study of hemin for treatment of AHP acute attacks collected data on hemin used to treat 305 presumed acute porphyria attacks (in 111 patients with a clinical diagnosis of acute porphyria by treating physician; mean age 40.3 years). Hemin was judged by the treating physicians to be successful for all attacks in 73% of patients (n=81); 85% (n=94) of patients had at least 1 treatment success, and 15% (n=17) had no successes. Of the 305 treatment courses for an acute attack, 266 (87%) were perceived as successful. However, there were no specific outcome measures used.

Tier 5

Additional management of acute attacks of AIP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia and hypomagnesemia, if present. Identifiable precipitating factors, such as medications, should be stopped. In acute attacks that present with seizures, management should be approached with caution because many anticonvulsant medications are contraindicated in AIP.

Tier 2

Prophylactic heme therapy or givosiran (a novel small interfering RNA-based therapy) administered in an outpatient setting, should be considered in patients with recurrent attacks (4 or more per year). Although hemin is effective at stopping acute attacks, its effectiveness in preventing recurrent attacks is less established. Recently, givosiran was approved for treatment of adults with AIP (United States) or person 12 years and older (European Union). In a phase 3, randomized, double-blinded, placebo-controlled study of patients with AHP (not separated by type) with recurrent attacks, monthly subcutaneous injections significantly lowered rates of acute attacks that correlated with lower urine ALA and PBG levels. A significant proportion of patients on givosiran were free of attacks. It has been suggested that givosiran only be given to patients with biochemically and genetically confirmed AHP. Given the limited safety data, givosiran should not be used in women who are pregnant or planning a pregnancy.

Tier 2

In mild attacks (mild pain, no vomiting, no paralysis, no hyponatremia), elimination of precipitating factors, a high carbohydrate diet with glucose containing drinks, and supportive and symptomatic therapy may be used alone or can be given while awaiting delivery of hemin. However, if neurological complications occur in the absence of other indicators of severity, treatment with hemin should be started immediately.

Tier 2

Regular meals and symptomatic treatment of nausea and loss of appetite are important to help ensure an adequate diet and avoid precipitation of an attack.

Tier 2

Patients should wear medical alert bracelets and carry wallet cards to notify emergency medical personnel and ensure that unsafe drugs are not given to patients in emergencies.

Tier 2

Individuals should seek timely treatment of systemic illness or infection.

Tier 4

Pre-operative anesthesia considerations in patients with AIP include:

• Consultation with an experienced anesthesiologist (including earlier in pregnancy for pregnant patients) in advance to better plan surgery and anesthesia management

• Consultation with physician with expertise in evaluation and management of AIP

• Consultation with neurologist if there are neurologic signs

• Urine sampling for preliminary staging of porphyria precursors

• No stress

• No starvation; maintenance of adequate intake of carbohydrates and energy (preoperative glucose supplementation)

• Avoidance of barbiturates and corticosteroids

• Avoid ambulatory anesthesia when possible.

Tier 4

Pregnancy management considerations for people with AIP include:

• Complications of pregnancy should be excluded when patients present with abdominal pain, hypertension and tachycardia, before the findings are attributed to an acute attack.

• Symptomatic treatment of an acute attack that occurs during pregnancy should take into account the potential for the medication to precipitate/exacerbate an acute attack of porphyria in the pregnant person and the potential risk of an adverse effect of the drug on the developing fetus.

• In an obstetric emergency, no drug should be restricted if it is likely to be of major clinical benefit or is required in a life-threatening situation.

Tier 4

Surveillance

Liver enzymes should be monitored annually for liver disease.

Tier 2

Patients with AIP, regardless of the severity of symptoms, should undergo surveillance for HCC, beginning at age 50 years, with liver ultrasound every 6 months. A case-control study of HCC screening in DNA-diagnosed individuals with AIP compared individuals with repeated screening intervals < 2 years to individuals who had never been screened, those screened for the first time, screened at intervals of >2 years, or dropouts. The screening group included 62 patients (mean age 67 years; range 50-83 years; 57% with a history of acute attacks) with 15 years follow up. Patients were screened every 1-1.5 years with liver CT, ultrasound or MRI. Over the 15 years of follow up 22 patients developed HCC, 8 from the screened group and 14 from the control group. Surgery was an option for 7/8 patients in the screened group compared to 4/14 patients in the control group (p=0.024). All individuals with HCC in the control group died during the study (all from HCC except for one prostate cancer) versus 2 patients from the screened group (1 from anaplastic pulmonary cancer and one from HCC). Those who underwent screening had significantly improved 3- and 5-year survival rates.

Tier 2

Patients with AIP on treatment should undergo surveillance for chronic kidney disease annually, and more frequently for those on givosiran, with serum creatinine and estimated glomerular filtration rate.

Tier 2

Circumstances to Avoid

Patients should be counseled to avoid identifiable triggers including alcohol, smoking, porphyrinogenic medications, caloric deprivation, and illicit drugs.

Tier 2

A retrospective population-based study in Sweden included 356 individuals with AIP. Among these individuals clinical manifestations of AIP were identified in 42%. Self-reported smoking was associated with high attack frequency (>10 attacks) (OR 1.62, CI 1.07-11.46) compared with non-smokers adjusted for age and gender. In addition, other self-reported triggers included medication use (20%), fasting (19%), physical strain (12%), psychological strain (31%), alcohol (14%), work environment (8%), infections (15%), menstruation (32%), and pregnancy (9%). However, authors note that the high prevalence of overt AIP in this study could be explained by a pathogenic variant dependent penetrance, since 89% of individuals had the same pathogenic variant.

Tier 5

In the longitudinal study of the US Porphyrias Consortium, of individuals with AIP (n=90), 37% of individuals reported ingestion of medications as triggers for acute attacks; 22% reported weight loss diets as triggers; 16% surgery; and 7% environmental toxins as other precipitating factors.

Tier 5

Prolonged fasting should be avoided during labor and delivery, as should the use of unsafe drugs, for example, ergometrine. Stress should be minimized by providing good analgesia in the form of spinal or epidural anesthesia using bupivacaine (which has been safely used).

Tier 4

Nature of Intervention

Nature of Intervention

Administration of hemin may cause a transient anticoagulant effect and often phlebitis at the site of infusion. Phlebitis can be severe and can compromise venous access with repeated administration. Other uncommon, reported side effects of hemin include fever, aching, malaise, or hemolysis. Rare cases of circulatory collapse and renal failure have been reported. Chronic hemin use is associated with several complications including the need for indwelling central venous catheters, infections, and iron overload.

Context: Adult Pediatric

An open label study of hemin administration for prophylaxis and acute attacks notes that 44% and 20% of patients experienced adverse and serious events, though most could be attributed to porphyria and not the treatment. These events were much more frequent in those patients treated only for acute attacks than in those only for prophylaxis.

Context: Adult Pediatric

Adverse events observed more frequently with givosiran were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions.

Context: Adult Pediatric

Hemin has been administered in pregnancy and appears to be safe.

Context: Adult Pediatric

Chance to Escape Clinical Detection

Recognition of an acute porphyria attack can be difficult as individual symptoms and signs are non-specific, particularly in the early stages. Delayed diagnosis (up to more than 15 years from initial presentation) and treatment may contribute to the higher death rate among those with AIP. Attacks usually do not begin until the third or fourth decade of life.

Context: Adult Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			HMBS			176000	0008294

References List

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Rapp H-J. Anaesthesia recommendations for patients suffering from Porphyria. Orphan Anesthesia (2009) URL: https://www.orphananesthesia.eu/en/rare-diseases/published-guidelines/porphyria/184-porphyria/file.html

SD Whatley, MN Badminton. Acute Intermittent Porphyria. (2005) [Updated Feb 07 2013]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1193/

Stein P, Badminton M, Barth J, Rees D, Stewart MF. (2013) Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Annals of clinical biochemistry. 50(Pt 3):217-23.

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