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Acute hepatic porphyria (AHP): how to diagnose early and ensure timely AHP management

Read time: 5 mins
Last updated:2nd Dec 2022
Published:28th Jan 2022

Key take-away points

  • Due to the relatively nonspecific nature of AHP symptoms and the rarity of the disease, diagnosis of AHP is too often missed
  • AHP may be suspected during an attack due to a combination of symptoms such as the ‘classic triad’ of acute unexplained abdominal pain, neuropathy, and neuropsychiatric disturbances. Patients with attacks will likely present in an emergency setting
  • For patients with current symptoms, confirming a diagnosis of AHP is relatively straightforward with a spot urine test for neurotoxins aminolevulinic acid (ALA) and porphobilinogen (PBG). In between attacks, a stool-sample should be collected as well
  • Early diagnosis is critical to prevent long-term neurological damage and chronic complications
  • For optimal management and advice contact a specialist porphyria centre or expert

Download this infographic on recognising and diagnosing AHP

What is acute hepatic porphyria?

Acute hepatic porphyria (AHP) refers to a family of rare diseases characterised by genetic defects in the individual enzymes of heme synthesis in the liver1. The defects lead to uncontrolled upregulation of a hepatic enzyme, aminolevulinic acid synthase 1, ALAS1. Induction of ALAS1 results in the increased production and accumulation of the neurotoxins porphobilinogen (PBG) and aminolevulinic acid (ALA).

Factors such as certain drugs, infections, caloric restriction (dieting, fasting), alcohol abuse and hormonal changes can trigger an AHP attack2.

Early AHP diagnosis is critical

Early AHP diagnosis is critical: delays in diagnosis and management increase the risk of serious acute and chronic complications, may lead to permanent neurological damage and can be potentially fatal3–5.

AHP attacks are difficult to diagnose because the clinical presentation is variable and there is no single pathognomonic sign for an acute porphyritic attack (Figure 1)2. While patients who experience severe attacks would likely present in an emergency setting, by understanding attack signs and symptoms general practitioners can be better informed to drive an early diagnosis based on patient medical history and understanding the disease during and between acute attacks2.

AHP - Fig1.png

Figure 1. Attack signs and symptoms of acute hepatic porphyria (AHP)4,6,7. Note that patients may present with any combination of these symptoms.

AHP is rare: the prevalence of gene mutations associated with AHP is only about 9 cases per million, and under 10% of carriers will have an acute attack2. However, AHP attacks are highly debilitating to patients and can result in long-term complications regardless of attack frequency2,8.

Chronic symptoms and long-term complications such as hypertension, chronic kidney disease, and liver cancer can occur regardless of attack frequency2,8.

Apart from the acute pain and distress suffered during acute attacks, patients may experience severe and sometimes irreversible neurological damage2. Prolonged periods of illness and recovery can reduce patient’s quality of life9, and cause financial stress9. Their lifelong risk of hypertension, kidney disease, and hepatocellular carcinoma also increases2.

Common misdiagnoses for AHP

The combination of nonspecific signs of an acute porphyritic attack mimics many conditions. Some common misdiagnoses in patients with AHP include7,10–14:

  • Acute abdomen conditions, irritable bowel syndrome and Crohn’s disease
  • Endometriosis
  • Psychiatric disorders, seizures and Guillain-Barre syndrome
  • Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), syndrome of inappropriate antidiuretic hormone secretion (SIADH), polyneuropathy and fibromyalgia

Avoiding misdiagnosis of AHP – the red flags

You can prevent irreversible neurological damage and chronic complications for patients by recognising AHP early and ensuring a timely AHP management.

Unexplained, recurrent abdominal pain is a red flag for AHP – nearly all patients have abdominal pain during AHP attacks2

Abdominal pain, along with various neuropathies and neuropsychiatric disturbances, form the 'classic triad' of AHP symptoms (Figure 2)2,15.

Hyponatraemia is also seen in up to one-third of patients with AHP, while 37–55% of patients with AHP present with dark urine7,16.

AHP - Fig2.png

Figure 2. Recognising and diagnosing acute hepatic porphyria (AHP) during an acute attack2,7,9,15. ALA, aminolevulinic acid; PBG, porphobilinogen.

Confirming an AHP diagnosis

For patients with current symptoms, a spot urine test can rapidly confirm or rule out AHP (Figure 2): an ALA or PBG level four times the upper limit of normal confirms the diagnosis2. Levels more than twice normal are suspicious and require further investigation2.

In an emergency situation in the hospital setting, a quick and simple urine colour test can be useful if there is a suspicion of AHP, since a change in urine colour under light is an indicator of the disease7,17,18

In between attacks, a stool-sample should be collected as well18.

Managing AHP and referrals

While acute AHP attacks are managed mostly in an emergency setting, AHP management after and between attacks is vital to minimise further attacks, prevent the development of severe or chronic neurological damage and reduce disease burden, and to improve the patient experience in living with this disease2. Management of AHP in general practice should include:

  • counselling about disease
    • avoid triggers: drugs, alcohol, smoking
    • develop an emergency plan
  • checking new prescriptions for safety
  • regular, lifelong monitoring of blood pressure and renal function
  • liver ultrasound for patients over 50 to monitor for hepatic carcinoma

Frequency of liver screening may differ in your location, and some medications can be triggers for porphyria, so for optimal management and advice contact your local specialist porphyria centre or expert2.

Download this infographic on recognising and diagnosing AHP

References

  1. Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Molecular Genetics and Metabolism. 2019;128(3):213–218.
  2. Neeleman RA, Wensink D, Wagenmakers MAEM, Mijnhout GS, Friesema ECH, Langendonk JG. Diagnostic and therapeutic strategies for porphyrias. Netherlands Journal of Medicine. 2020;78(4):149–160.
  3. Simon A, Pompilus F, Querbes W, Wei A, Strzok S, Penz C, et al. Patient Perspective on Acute Intermittent Porphyria with Frequent Attacks: A Disease with Intermittent and Chronic Manifestations. The Patient. 2018;11(5):527.
  4. Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Annals of internal medicine. 2005;142(6):439–450.
  5. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. The New England journal of medicine. 2017;377(9):862–872.
  6. Balwani M, Wang B, Anderson KE, Bloomer JR, Bissell DM, Bonkovsky HL, et al. Acute hepatic porphyrias: Recommendations for evaluation and long-term management. Hepatology (Baltimore, Md). 2017;66(4):1314–1322.
  7. Ventura P, Cappellini MD, Biolcati G, Guida CC, Rocchi E, Graziadei G, et al. A challenging diagnosis for potential fatal diseases: recommendations for diagnosing acute porphyrias. European journal of internal medicine. 2014;25(6):497–505.
  8. Buendía-Martínez J, Barreda-Sánchez M, Rodríguez-Peña L, Ballesta-Martínez MJ, López-González V, Sánchez-Soler MJ, et al. Health impact of acute intermittent porphyria in latent and non-recurrent attacks patients. Orphanet Journal of Rare Diseases. 2021;16(1):1–8.
  9. Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stölzel U, et al. EXPLORE: A prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology (Baltimore, Md). 2020;71(5):1546–1558.
  10. Alfadhel M, Saleh N, Alenazi H, Baffoe-Bonnie H. Acute intermittent porphyria caused by novel mutation in HMBS gene, misdiagnosed as cholecystitis. Neuropsychiatric Disease and Treatment. 2014;10:2135–2137.
  11. Ali F, Kumar N, Dyck PJB, Berini S, Klaas J. Porphyria: A rare differential diagnosis of polyradiculoneuropathy. Journal of the Neurological Sciences. 2019;402:153–155.
  12. Anderson KE. Acute hepatic porphyrias: Current diagnosis & management. Molecular Genetics and Metabolism. 2019;128(3):219–227.
  13. Sieg I, Beckh K, Kersten U, Doss MO. Manifestation of acute intermittent porphyria in patients with chronic inflammatory bowel disease. Zeitschrift fur Gastroenterologie. 1991;29(11):602–605.
  14. Findley H, Bmed B, Frca S, Philips A, Frca M, Cole D, et al. Porphyrias: implications for anaesthesia, critical care, and pain medicine. Continuing Education in Anaesthesia Critical Care & Pain. 2012;12(3):128–133.
  15. Simon N, Herkes G. The neurologic manifestations of the acute porphyrias. Journal of clinical neuroscience. 2011;18(9):1147–1153.
  16. Anderson KE, Desnick RJ, Stewart MF, Ventura P, Bonkovsky HL. Acute Hepatic Porphyrias: “Purple Flags”-Clinical Features that should Prompt Specific Diagnostic Testing. The American Journal of the Medical Sciences. 2021. doi:10.1016/J.AMJMS.2021.09.009.
  17. Ventura P, Cappellini MD, Rocchi E. The acute porphyrias: A diagnostic and therapeutic challenge in internal and emergency medicine. Internal and Emergency Medicine. 2009;4(4):297–308.
  18. Stein PE, Badminton MN, Rees DC. Update review of the acute porphyrias. British Journal of Haematology. 2017;176(4):527–538.
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