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AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review

2023; Elsevier BV; Volume: 164; Issue: 3 Linguagem: Inglês

10.1053/j.gastro.2022.11.034

1528-0012

Bruce Wang, Herbert L. Bonkovsky, Joseph K. Lim, Manisha Balwani,

Folate and B Vitamins Research

DescriptionThe acute hepatic porphyrias (AHP) are rare, inborn errors of heme-metabolism and include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and porphyria due to severe deficiency of 5-aminolevulinic acid dehydratase. Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of approximately 1 in 100,000. The major clinical presentation involves attacks of severe pain, usually abdominal and generalized, without peritoneal signs or abnormalities on cross-sectional imaging. Acute attacks occur mainly in women in their childbearing years. AHP should be considered in the evaluation of all patients, and especially women aged 15–50 years with recurrent severe abdominal pain not ascribable to common causes. The screening tests of choice include random urine porphobilinogen and δ-aminolevulinic acid corrected to creatinine. All patients with elevations in urinary porphobilinogen and/or δ-aminolevulinic acid should initially be presumed to have AHP. The cornerstones of management include discontinuation of porphyrinogenic drugs and chemicals, administration of oral or intravenous dextrose and intravenous hemin, and use of analgesics and antiemetics. Diagnosis of AHP type can be confirmed after initial treatment by genetic testing for pathogenic variants in HMBS, CPOX, PPOX, and ALAD genes. AHP is also associated with chronic symptoms and long-term risk of systemic arterial hypertension, chronic renal and liver disease, and hepatocellular carcinoma. Patients who have recurrent acute attacks (4 or more per year) should be considered for prophylactic therapy with intravenous hemin or subcutaneous givosiran. Liver transplantation is curative and reserved for patients with intractable symptoms who have failed other treatment options.MethodsThis expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations.Best Practice Advice StatementsBest Practice Advice 1Women aged 15–50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup should be considered for screening for an AHP.Best Practice Advice 2Initial diagnosis of AHP should be made by biochemical testing measuring δ-aminolevulinic acid, porphobilinogen, and creatinine on a random urine sample.Best Practice Advice 3Genetic testing should be used to confirm the diagnosis of AHP in patients with positive biochemical testing.Best Practice Advice 4Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein.Best Practice Advice 5In addition to intravenous hemin, management of acute attacks of AHP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia, and hypomagnesemia, if present.Best Practice Advice 6Patients should be counseled to avoid identifiable triggers that may precipitate acute attacks, such as alcohol and porphyrinogenic medications.Best Practice Advice 7Prophylactic heme therapy or givosiran, administered in an outpatient setting, should be considered in patients with recurrent attacks (4 or more per year).Best Practice Advice 8Liver transplantation for AHP should be limited to patients with intractable symptoms and significantly decreased quality of life who are refractory to pharmacotherapy.Best Practice Advice 9Patients with AHP should be monitored annually for liver disease.Best Practice Advice 10Patients with AHP, regardless of the severity of symptoms, should undergo surveillance for hepatocellular carcinoma, beginning at age 50 years, with liver ultrasound every 6 months.Best Practice Advice 11Patients with AHP on treatment should undergo surveillance for chronic kidney disease annually with serum creatinine and estimated glomerular filtration rate.Best Practice Advice 12Patients should be counseled on the chronic and long-term complications of AHP, including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma, and need for long-term monitoring. The acute hepatic porphyrias (AHP) are rare, inborn errors of heme-metabolism and include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and porphyria due to severe deficiency of 5-aminolevulinic acid dehydratase. Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of approximately 1 in 100,000. The major clinical presentation involves attacks of severe pain, usually abdominal and generalized, without peritoneal signs or abnormalities on cross-sectional imaging. Acute attacks occur mainly in women in their childbearing years. AHP should be considered in the evaluation of all patients, and especially women aged 15–50 years with recurrent severe abdominal pain not ascribable to common causes. The screening tests of choice include random urine porphobilinogen and δ-aminolevulinic acid corrected to creatinine. All patients with elevations in urinary porphobilinogen and/or δ-aminolevulinic acid should initially be presumed to have AHP. The cornerstones of management include discontinuation of porphyrinogenic drugs and chemicals, administration of oral or intravenous dextrose and intravenous hemin, and use of analgesics and antiemetics. Diagnosis of AHP type can be confirmed after initial treatment by genetic testing for pathogenic variants in HMBS, CPOX, PPOX, and ALAD genes. AHP is also associated with chronic symptoms and long-term risk of systemic arterial hypertension, chronic renal and liver disease, and hepatocellular carcinoma. Patients who have recurrent acute attacks (4 or more per year) should be considered for prophylactic therapy with intravenous hemin or subcutaneous givosiran. Liver transplantation is curative and reserved for patients with intractable symptoms who have failed other treatment options. This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements Women aged 15–50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup should be considered for screening for an AHP. Initial diagnosis of AHP should be made by biochemical testing measuring δ-aminolevulinic acid, porphobilinogen, and creatinine on a random urine sample. Genetic testing should be used to confirm the diagnosis of AHP in patients with positive biochemical testing. Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein. In addition to intravenous hemin, management of acute attacks of AHP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia, and hypomagnesemia, if present. Patients should be counseled to avoid identifiable triggers that may precipitate acute attacks, such as alcohol and porphyrinogenic medications. Prophylactic heme therapy or givosiran, administered in an outpatient setting, should be considered in patients with recurrent attacks (4 or more per year). Liver transplantation for AHP should be limited to patients with intractable symptoms and significantly decreased quality of life who are refractory to pharmacotherapy. Patients with AHP should be monitored annually for liver disease. Patients with AHP, regardless of the severity of symptoms, should undergo surveillance for hepatocellular carcinoma, beginning at age 50 years, with liver ultrasound every 6 months. Patients with AHP on treatment should undergo surveillance for chronic kidney disease annually with serum creatinine and estimated glomerular filtration rate. Patients should be counseled on the chronic and long-term complications of AHP, including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma, and need for long-term monitoring. Porphyrias are inherited disorders in the heme biosynthesis pathway. Heme is an essential molecule that carries out a wide array of functions necessary for aerobic life. It is synthesized through 8 enzymatic steps, and mutations that lead to partially defective activity in heme synthesis enzymes result in the 8 inherited porphyrias.1Bissell D.M. Anderson K.E. Bonkovsky H.L. Porphyria. N Engl J Med. 2017; 377: 862-872Crossref PubMed Scopus (242) Google Scholar,2Puy H. Gouya L. Deybach J.C. Porphyrias. Lancet. 2010; 375: 924-937Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar Symptoms are due to the specific intermediates that accumulate before the defective enzymatic step. The acute hepatic porphyrias (AHPs) include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and 5-aminolevulinic acid dehydratase deficiency porphyria (ALAD) (Table 1). They present with acute neurovisceral symptoms due to abnormal accumulation of the porphyrin precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). Clinically, they present with severe acute abdominal pain, nausea, vomiting, constipation, muscle weakness, neuropathy, tachycardia, and hypertension. Four additional porphyrias present primarily with cutaneous symptoms and are not discussed in this review.Table 1Summary of Acute Hepatic PorphyriasAHP typeInheritanceAge at presentationGender predominanceSymptoms and signsAIPAD15–50 yF > MAcuteHCPAD15–50 yF > MAcute, cutaneousVPAD15–50 yF > MAcute, cutaneousALADARChildhood-adulthoodM > FAcuteAD, autosomal dominant; AR, autosomal recessive; F, female; M, male. Open table in a new tab AD, autosomal dominant; AR, autosomal recessive; F, female; M, male. AIP, HCP, and VP are autosomal dominant disorders and ALAD porphyria is a very rare autosomal recessive disorder with fewer than a dozen reported cases in the world literature.3Doss M. von Tieperman R. Schneider J. et al.New type of hepatic porphyria with porphobilinogen synthase defect and intermittent acute clinical manifestation.Klin Wochenschr. 1979; 57: 1123-1127Crossref PubMed Scopus (131) Google Scholar, 4Doss M.O. Stauch T. Gross U. et al.The third case of Doss porphyria (delta-amino-levulinic acid dehydratase deficiency) in Germany.J Inherit Metab Dis. 2004; 27: 529-536Crossref PubMed Scopus (38) Google Scholar, 5Thunell S. Holmberg L. Lundgren J. Aminolaevulinate dehydratase porphyria in infancy. A clinical and biochemical study.J Clin Chem Clin Biochem. 1987; 25: 5-14PubMed Google Scholar, 6Akagi R. Kato N. Inoue R. et al.delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations.Mol Genet Metab. 2006; 87: 329-336Crossref PubMed Scopus (40) Google Scholar Pathogenic variants in the hydroxymethylbilane synthase (HMBS), coproporphyrinogen oxidase, and protoporphyrinogen oxidase genes (referred to collectively as AHP pathogenic variants) result in at least a 50% reduction of the activity in the corresponding enzyme. Symptomatic AHPs are thought to affect approximately 1 in 100,000 patients; however, data from population-level genetic studies showed that the prevalence of pathogenic variants for AIP is between 1 in 1300 and 1 in 1785, much higher than previously believed.7Lenglet H. Schmitt C. Grange T. et al.From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria.Hum Mol Genet. 2018; 27: 1164-1173Crossref PubMed Scopus (65) Google Scholar,8Chen B. Solis-Villa C. Hakenberg J. et al.Acute intermittent porphyria: predicted pathogenicity of HMBS variants indicates extremely low penetrance of the autosomal dominant disease.Hum Mutat. 2016; 37: 1215-1222Crossref PubMed Scopus (126) Google Scholar Diagnoses of AHPs are often missed, with a delay of more than 15 years from initial presentation. This suggests that the true prevalence of symptomatic AHPs may be higher. Recent advances in treatment have improved the outlook for patients with AHP. This review is designed to provide best practice advice on the diagnosis, treatment, and long-term management of patients with AHP. We have developed Best Practice Advice statements to address 12 key clinical issues. Best Practice Advice 1: Women aged 15–50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup should be considered for screening for an AHP. 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. Attacks are often precipitated by inducing factors that increase heme production in the liver. An estimated 3%–5% of patients with symptomatic AHP experience frequent recurrent attacks, typically defined as 4 or more attacks per year. These attacks are often not associated with identifiable triggers, although some attacks during the luteal phase of the menstrual cycles are believed to be triggered by progesterone. 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.9Wang B. Ventura P. Takase K.-I. et al.Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study.Orphanet J Rare Dis. 2022; 17: 327Crossref PubMed Scopus (7) Google Scholar,10Gouya L. Ventura P. Balwani M. et al.EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks.Hepatology. 2020; 71: 1546-1558Crossref PubMed Scopus (91) Google Scholar These patients have a markedly impaired quality of life11Simon A. Pompilus F. Querbes W. et al.Patient perspective on acute intermittent porphyria with frequent attacks: a disease with intermittent and chronic manifestations.Patient. 2018; 11: 527-537Crossref PubMed Scopus (49) Google Scholar,12Naik H. Stoecker M. Sanderson S.C. et al.Experiences and concerns of patients with recurrent attacks of acute hepatic porphyria: a qualitative study.Mol Genet Metab. 2016; 119: 278-283Crossref PubMed Scopus (59) Google Scholar and are at higher risk of long-term complications of AHP, including hepatocellular carcinoma (HCC)13Peoc'h K. Manceau H. Karim Z. et al.Hepatocellular carcinoma in acute hepatic porphyrias: a Damocles sword.Mol Genet Metab. 2019; 128: 236-241Crossref PubMed Scopus (31) Google Scholar and chronic renal failure.14Sardh E. Andersson D.E.H. Henrichson A. et al.Porphyrin precursors and porphyrins in three patients with acute intermittent porphyria and end-stage renal disease under different therapy regimes.Cell Mol Biol (Noisy-le-grand). 2009; 55: 66-71PubMed Google Scholar,15Pallet N. Mami I. Schmitt C. et al.High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria.Kidney Int. 2015; 88: 386-395Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar ALA and PBG levels in patients experiencing recurrent attacks may be elevated at baseline between attacks.16Sardh E. Harper P. Balwani M. et al.Phase 1 trial of an RNA interference therapy for acute intermittent porphyria.N Engl J Med. 2019; 380: 549-558Crossref PubMed Scopus (190) Google Scholar It remains unclear whether chronic symptoms are due to persistently elevated ALA or incomplete recovery from neurologic injury sustained during acute attacks. Some individuals who carry an AHP pathogenic variant have elevated ALA and PBG but have never experienced acute attacks. This group of asymptomatic high excretors may be at increased risk for an induced acute attack, chronic renal or hepatic injury, and/or HCC relative to mutation carriers with normal ALA.17Sardh E. Wahlin S. Björnstedt M. et al.High risk of primary liver cancer in a cohort of 179 patients with acute hepatic porphyria.J Inherit Metab Dis. 2013; 36: 1063-1071Crossref PubMed Scopus (57) Google Scholar,18Andant C. Puy H. Bogard C. et al.Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors.J Hepatol. 2000; 32: 933-939Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Diagnosis of AHPs is frequently delayed, with an average of 15 years from onset of symptomatic AHP to diagnosis in the United States and Europe.19Bonkovsky H.L. Maddukuri V.C. Yazici C. et al.Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium.Am J Med. 2014; 127: 1233-1241Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Accordingly, AHP should be considered in any patient, especially any woman of childbearing age, who presents with unexplained recurrent, severe abdominal pain. Best Practice Advice 2: Initial diagnosis of AHP should be made by biochemical testing measuring ALA, PBG, and creatinine in a random urine sample. Diagnosis of symptomatic AHP requires biochemical testing (Figure 1). The hallmark of acute attacks is significantly elevated ALA and PBG in the urine or plasma. In all AHP except ALAD porphyria, PBG is elevated. During acute attacks, both ALA and PBG are elevated at least 5-fold the upper limit of normal. The levels are high enough that a random urine sample is sufficient and a 24-hour urine collection is not recommended. To adjust for differences in the degree of urinary concentration, ALA and PBG excretion should be normalized to that of creatinine. It is important to note that because ALA and PBG are porphyrin precursors, they are not included in tests of porphyrins, which typically measure porphyrins in urine or stool that have been separated and quantified by high-performance liquid chromatography with fluorescence detection. Urine porphyrins should not be used alone as a screening test for AHP. Mild and nondiagnostic elevations in urinary porphyrins (secondary porphyrinurias) are often incorrectly interpreted as indicating AHP and lead to erroneous overdiagnosis. Both ALA and PBG can be measured with high sensitivity and specificity.20Davis J.R. Andelman S.L. Urinary delta-aminolevulinic acid (ALA) levels in lead poisoning. I. A modified method for the rapid determination of urinary delta-aminolevulinic acid using disposable ion-exchange chromatography columns.Arch Environ Health. 1967; 15: 53-59Crossref PubMed Scopus (142) Google Scholar, 21Zhang J. Yasuda M. Desnick R.J. et al.A LC-MS/MS method for the specific, sensitive, and simultaneous quantification of 5-aminolevulinic acid and porphobilinogen.J Chromatogr B Analyt Technol Biomed Life Sci. 2011; 879: 2389-2396Crossref PubMed Scopus (36) Google Scholar, 22Benton C.M. Couchman L. Marsden J.T. et al.Direct and simultaneous quantitation of 5-aminolaevulinic acid and porphobilinogen in human serum or plasma by hydrophilic interaction liquid chromatography-atmospheric pressure chemical ionization/tandem mass spectrometry.Biomed Chromatogr. 2013; 27: 267-272Crossref PubMed Scopus (13) Google Scholar Unfortunately, these tests are performed at large reference laboratories only, and results often require 1–2 weeks to be reported. Rapid, qualitative urine PBG tests have been available since the 1950s (Hoesch or Watson-Schwartz test),23Pierach C.A. Cardinal R. Bossenmaier I. et al.Comparison of the Hoesch and the Watson-Schwartz tests for urinary porphobilinogen.Clin Chem. 1977; 23: 1666-1668Crossref PubMed Scopus (26) Google Scholar but their clinical use has been limited due to lack of use by most hospitals. Recently, a new rapid test for PBG was approved in the United States (Teco Diagnostics). For most patients with AHP, those who experience only a few acute attacks in their lifetimes, testing for urine ALA, PBG, and creatinine is most useful during an acute attack. Unless the patient has been treated with intravenous hemin, testing for ALA and PBG can be performed days after the acute attack. Studies of patients with AIP found that ALA and PBG can remain elevated in urine for months to years after an acute attack.24Marsden J.T. Rees D.C. Urinary excretion of porphyrins, porphobilinogen and delta-aminolaevulinic acid following an attack of acute intermittent porphyria.J Clin Pathol. 2014; 67: 60-65Crossref PubMed Scopus (54) Google Scholar However, ALA and PBG levels can fall quickly after an acute attack in patients with HCP or VP. When testing is performed in patients with sporadic AIP when they are asymptomatic, 15%–44% can have normal urine ALA and PBG values.25Andersson C. Thunell S. Floderus Y. et al.Diagnosis of acute intermittent porphyria in northern Sweden: an evaluation of mutation analysis and biochemical methods.J Intern Med. 1995; 237: 301-308Crossref PubMed Scopus (47) Google Scholar,26Kauppinen R. Von und zu Fraunberg M. Molecular and biochemical studies of acute intermittent porphyria in 196 patients and their families.Clin Chem. 2002; 48: 1891-1900Crossref PubMed Scopus (90) Google Scholar The same, or even higher, percentages are likely true for HCP and VP. In these patients, confirmatory testing may require repeat testing during an acute attack. In the small population of patients with AHP with recurrent acute attacks, urine ALA and PBG are typically elevated even at baseline between acute attacks.16Sardh E. Harper P. Balwani M. et al.Phase 1 trial of an RNA interference therapy for acute intermittent porphyria.N Engl J Med. 2019; 380: 549-558Crossref PubMed Scopus (190) Google Scholar In patients who have frequent symptoms suggestive of acute attacks, normal ALA and PBG levels likely rule out AHP as the etiology of the symptoms. Best Practice Advice 3: Genetic testing should be used to confirm the diagnosis of AHP in patients with positive biochemical testing. Once the biochemical tests indicate AHP, confirmation of the specific type of AHP is usually established by genetic testing, with sequencing of the 4 genes ALAD, HMBS, CPOX, and PPOX leading to ALAD, AIP, HCP, and VP, respectively. When whole-gene sequencing is performed, 95%–99% of cases can be identified.27Whatley S.D. Mason N.G. Woolf J.R. et al.Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene.Clin Chem. 2009; 55: 1406-1414Crossref PubMed Scopus (67) Google Scholar First-degree family members should be screened with genetic testing once the familial pathogenic variant has been identified in the patient with AHP to identify patients at risk for acute attacks. Those who are mutation carriers should be counseled. Although genetic testing is the gold standard for confirmation of diagnosis, it is not recommended for initial screening. Most carriers of pathogenic variants in AHP genes do not experience symptomatic acute attacks in their lifetimes. The estimated phenotypic penetrance of symptomatic disease is approximately 1% of AIP gene carriers,8Chen B. Solis-Villa C. Hakenberg J. et al.Acute intermittent porphyria: predicted pathogenicity of HMBS variants indicates extremely low penetrance of the autosomal dominant disease.Hum Mutat. 2016; 37: 1215-1222Crossref PubMed Scopus (126) Google Scholar with a penetrance of >20% in families with symptomatic patients.7Lenglet H. Schmitt C. Grange T. et al.From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria.Hum Mol Genet. 2018; 27: 1164-1173Crossref PubMed Scopus (65) Google Scholar HCP and VP are reported to have lower penetrance than AIP.28Hift R.J. Meissner P.N. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity.Medicine (Baltimore). 2005; 84: 48-60Crossref PubMed Scopus (123) Google Scholar Even among patients with a confirmed pathogenic variant, attribution of clinical symptoms often benefits from biochemical confirmation (Table 2).Table 2Testing Recommendations for Acute Hepatic PorphyriasDiagnostic biochemical testingConfirmatory testingAnnual MonitoringMonitoring on heminaAdditional tests for patients receiving prophylactic hemin therapy or givosiran.Monitoring on givosiranaAdditional tests for patients receiving prophylactic hemin therapy or givosiran.,bWe advise that the listed tests be performed before the start of givosiran and again just before each monthly injection of givosiran for 3 months. If the laboratory test results are stable and the drug is being well-tolerated, we advise that laboratory monitoring be repeated once every 3 months for the next year and at least once every 6 months thereafter.Random urine PBG, ALA, and creatininecSample should be normalized to creatinine, levels should be >5-fold the upper limit of normal for diagnosis. In 5-aminolevulinic acid dehydratase only ALA is elevated.Genetic testing by sequencingALAD, HMBS, CPOX, and PPOXLiver enzymes, creatinine and eGFR, liver ultrasound, and α-fetoprotein every 6 mo after age 50 yIron, ferritinComprehensive metabolic panel, plasma homocysteine urinalysis; urinary protein to creatinine ratio, B12/folate, amylase/lipasea Additional tests for patients receiving prophylactic hemin therapy or givosiran.b We advise that the listed tests be performed before the start of givosiran and again just before each monthly injection of givosiran for 3 months. If the laboratory test results are stable and the drug is being well-tolerated, we advise that laboratory monitoring be repeated once every 3 months for the next year and at least once every 6 months thereafter.c Sample should be normalized to creatinine, levels should be >5-fold the upper limit of normal for diagnosis. In 5-aminolevulinic acid dehydratase only ALA is elevated. Open table in a new tab Best Practice Advice 4: Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein. The currently approved treatment for acute attacks is intravenous hemin infusion,29Bissell D.M. Treatment of acute hepatic porphyria with hematin.J Hepatol. 1988; 6: 1-7Abstract Full Text PDF PubMed Scopus (48) Google Scholar, 30Stein J.A. Tschudy D.P. Acute intermittent porphyria. A clinical and biochemical study of 46 patients.Medicine (Baltimore). 1970; 49: 1-16Crossref PubMed Scopus (231) Google Scholar, 31Bonkowsky H.L. Tschudy D.P. Collins A. et al.Repression of the overproduction of porphyrin precursors in acute intermittent porphyria by intravenous infusions of hematin.Proc Natl Acad Sci U S A. 1971; 68: 2725-2729Crossref PubMed Scopus (173) Google Scholar, 32Lamon J.M. Frykholm B.C. Hess R.A. et al.Hematin therapy for acute porphyria.Medicine (Baltimore). 1979; 58: 252-269Crossref PubMed Scopus (83) Google Scholar, 33Watson C.J. Pierach C.A. Bossenmaier I. et al.Postulated deficiency of hepatic heme and repair by hematin infusions in the "inducible" hepatic porphyrias.Proc Natl Acad Sci U S A. 1977; 74: 2118-2120Crossref PubMed Scopus (40) Google Scholar usually given once daily at a dose of 3–4 mg/kg body weight, typically for 4 days. Hemin rapidly down-regulates ALAS1 expression in the liver, thus ameliorating the continued overproduction and accumulation of ALA and PBG. Symptom relief depends on elimination of excess ALA and PBG and typically requires 48–72 hours, although recovery from neurologic symptoms can vary significantly. Timely initiation of hemin therapy results in normalization of ALA and PBG levels, symptom improvement, and decreased risk of long-term neurologic complications. A random urine for ALA, PBG, and creatinine should be collected before the start of hemin treatment. Due to the lack of available rapid ALA or PBG tests, initiation of hemin can be made on empirical grounds in patients with confirmed AHP. Because of potential thrombophlebitis from hemin, it is best given into a high-flow central vein via a peripherally inserted central catheter or central port. In addition, heme bound to human serum albumin is preferred due to heme stabilization and less irritation to veins.34Anderson K.E. Bonkovsky H.L. Bloomer J.R. et al.Reconstitution of hematin for intravenous infusion.Ann Intern Med. 2006; 144: 537-538Crossref PubMed Scopus (44) Google Scholar Best Practice Advice 5: In addition to intravenous hemin, management of acute attacks of AHP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia and hypomagnesemia, if present. The primary goal of treatment during an acute attack is to decrease ALA pr