Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.0.4
• GENE/GENE PANEL: HMBS
• Condition: Acute Intermittent Porphyria
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• HMBS ⇔ 176000: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Neurovisceral attacks / Optimal clinical management to reduce risk of attacks (e.g., avoidance of harmful medications, dietary advice, treatment of infections, avoidance of smoking/alcohol)	2	2C	2B	3	9CB
Hepatocellular carcinoma / Liver US surveillance	2	2C	3C 1	3	10CC
Morbidity of acute attacks / Optimal treatment (Hemin) in the event of an attack	2	2C	3B	3	10CB

1. Scores where the tier of evidence recommendation of the working group differs from the evidence level tier in the Summary Report.

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence estimates for acute intermittent porphyria (AIP) across all European countries (excluding Sweden) range from 5.4-5.9/1,000,000. In Sweden, the incidence and prevalence of AIP are about 4 times higher than in Europe due to a founder effect. [1, 2, 3]

Clinical Features

AIP results from half normal activity of the enzyme hydroxymethylbilane synthase (HMBS) involved in the biosynthesis of heme. The condition is characterized by intermittent and sometimes life-threatening acute neurovisceral attacks of severe abdominal pain without peritoneal signs. These attacks may be accompanied by nausea, vomiting, distention, constipation, diarrhea, tachycardia, hypertension, and hyponatremia. 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). 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. [3, 4, 5, 6]

Natural History

Attacks rarely occur before puberty, usually beginning in the third or fourth decade of life. Attacks are more common in women than men, with acute attacks in women usually related to the menstrual cycle. Most symptomatic individuals with AIP have one or a few attacks. Approximately 5% of patients (mainly women) have recurrent attacks (defined as >4 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. Long term complications can include chronic renal failure, hepatocellular carcinoma (HCC), and hypertension. 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. While all individuals with a mutation in HMBS are predisposed to acute attacks, most never have symptoms and are said to have latent (or presymptomatic AIP). The risk that an individual with latent AIP will later develop symptoms depends on age, sex, exposure to provoking agents, and other factors. 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. [3, 4, 5, 6]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs in an individual diagnosed with acute AIP the
following evaluations are recommended:
• Full clinical history and examination, including neurologic evaluation if symptomatic
• Review of medications to assess risk versus benefit
• Quantitation of urine porphobilinogen 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
• Referral to clinical genetics for counseling (Tier 4) [3]

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) [4, 7]

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) [4]

Individuals should seek timely treatment of systemic illness or infection. (Tier 4) [3]

Specific treatment is indicated only in patients with clinical features of an acute attack and increased excretion of porphobilinogen in the urine. In mild attacks (mild pain, no vomiting, no paralysis, no hyponatremia), elimination of precipitating factors, a high carbohydrate diet, and supportive and symptomatic therapy may be used alone or can be given while awaiting delivery of hemin. Hemin therapy should be started early for most acute attacks, including patients with neuropathy. 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 and found striking decreases in urinal porphobilinogen 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 and 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) [4, 7]

Surveillance

Periodic (annual) liver ultrasound should be considered for individuals aged >50 years with previous overt or asymptomatic disease who ask to be tested after careful discussion of the likely risks and benefits. A case-control study of HCC screening in DNA-diagnosed AIP carriers included 62 patients (57% with a history of acute attacks) with 15 years follow up. Patients were screened every 1-1.5 years and were compared with gene carriers who had never been screened, screened for the first time, screened at intervals of >2 years, or drop outs. Over the 15 years of follow up 22 patients developed HCC. 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. An excess risk of hepatocellular cancer has been reported in Swedish patients with API. As Sweden has a relatively high prevalence of AIP due to a founder effect, it is uncertain to what extent the finding is generalizable to other populations and whether early intervention through screening can improve outcomes. (Tier 2) [8, 9]

Circumstances to Avoid

Patients should avoid alcohol, smoking, medications, and illicit drugs that can induce exacerbations. (Tier 2) [4, 7]

A retrospective population based study in Sweden included 356 gene carriers. Among these patients 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%). (Tier 5) [10]

A study of 145 Finnish patients with AIP found that almost all of these patients had been exposed to prescription drugs or anesthetics included in the lists of unsafe drugs and use was never associated with an acute attack. Among 37 individuals reporting alcohol use only 3 reported an acute attack related to drinking; however, a majority reported some milder symptoms with heavy drinking being more risky. (Tier 5) [11]

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) [3]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

The prevalence of the genetic mutation is estimated at 1-2 per 10,000 in Europe. Some countries, including Sweden have a higher prevalence due to founder effects in those populations. [8]

Penetrance

The penetrance for clinical manifestations of an HMBS pathogenic variant is not accurately known.
Approximately 80% of carriers of a gene mutation remain asymptomatic and others may have only 1 or a few acute attacks throughout life. (Tier 2) [4]

In one study of Swiss patients, 52% of relatives ascertained through cascade screening were found to have "typical" clinical symptoms. However, most reviews written by experienced porphyria specialists quote a penetrance, by which they imply an acute attack, leading to a hospital admission for medical management, of 10%-20%. Population surveys suggest a lower figure (e.g. a penetrance estimate of about 1% in France.) (Tier 3) [3]

One retrospective study of mortality in a US population of 136 patients with AIP over a 50-year period did not identify any cases of HCC, but follow-up data were not available in 22% of this cohort. An increased incidence of HCC has been reported for patients with AIP in a large prospective study in France with 5 cases of HCC developing among 430 patients over 7 years. In Switzerland, two cases of HCC occurred among 205 subjects with AIP during a 15-year period. The largest increase in risk for HCC appears to occur in Swedish patients with one 15 year prospective study identifying HCC among 22 of the 62 AIP gene carriers participating in regular screening. A recent prospective study identified a 63 - fold greater incidence per million inhabitants of this complication of AIP in Sweden than in the other countries (France, Netherlands, Switzerland, UK). (Tier 3) [8]

Information on the penetrance of variants was not available for the Adult context.

Relative Risk

No information on relative risk was identified.

Expressivity

Attacks are highly variable within and between individuals. (Tier 4) [3]

4. What is the Nature of the Intervention?

Nature of Intervention

Recommended interventions include period liver ultrasound and avoidance of circumstances that may precipitate an attack.
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. [4]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Delayed diagnosis 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. [4, 3]

Date of Search: 09.14.2016

Reference List

1. OrphaNet. Prevalence of rare diseases. Publisher: OrphaNet. (2016) Website: http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf

2. Elder G, Harper P, Badminton M, Sandberg S, Deybach JC. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis. (2013) 36(5):849-57.

3. SD Whatley, MN Badminton. Acute Intermittent Porphyria. 2005 Sep 27 [Updated 2013 Feb 07]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1193

4. Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR, Desnick RJ. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. (2005) 142(6):439-50.

5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. PORPHYRIA, ACUTE INTERMITTENT; AIP. MIM: 176000: 2016 Jul 09. World Wide Web URL: http://omim.org.

6. Acute intermittent porphyria. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=79276

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

8. Stewart MF. Review of hepatocellular cancer, hypertension and renal impairment as late complications of acute porphyria and recommendations for patient follow-up. J Clin Pathol. (2012) 65(11):976-80.

9. Innala E, Andersson C. Screening for hepatocellular carcinoma in acute intermittent porphyria: a 15-year follow-up in northern Sweden. J Intern Med. (2011) 269(5):538-45.

10. Bylesjo I, Wikberg A, Andersson C. Clinical aspects of acute intermittent porphyria in northern Sweden: a population-based study. Scand J Clin Lab Invest. (2009) 69(5):612-8.

11. Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore). (1992) 71(1):1-13.