Understanding Hepatic Porphyrias: Symptoms, Treatments, and Unmet Needs.

Hepatic porphyrias are a group of metabolic disorders that are characterized by overproduction and accumulation of porphyrin precursors in the liver. These porphyrins cause neurologic symptoms as well as cutaneous photosensitivity, and in some cases patients can experience life-threatening acute neurovisceral attacks. This review describes the acute hepatic porphyrias in detail, including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, as well as the hepatic porphyrias with cutaneous manifestations such as porphyria cutanea tarda and hepatoerythropoietic porphyria. Each section will cover disease prevalence, clinical manifestations, and current therapies, including strategies to manage symptoms. Finally, we review new and emerging treatment modalities, including gene therapy through use of adeno-associated vectors and chaperone therapies such as lipid nanoparticle and small interfering RNA-based therapeutics.

Hyperhomocysteinemia in acute hepatic porphyria (AHP) and implications for treatment with givosiran.

INTRODUCTION: Homocysteine is a sulfur-containing amino acid formed in the intermediary metabolism of methionine. Amino acid metabolism and heme biosynthesis pathways are complexly intertwined. Plasma homocysteine elevation, hyperhomocysteinemia (HHcy), has been reported in patients with acute hepatic porphyria (AHP), a family of rare genetic disorders caused by defects in hepatic heme biosynthesis. AREAS COVERED: This article summarizes published case series in which givosiran, a subcutaneously administered small interfering RNA approved for AHP treatment, appeared to exacerbate dysregulated homocysteine metabolism in patients with AHP. A comprehensive exploratory analysis of ENVISION trial data demonstrated that on a population level, givosiran increased homocysteine but with wide interpatient variations, and there is no proof of correlations between HHcy and changes in efficacy or safety of givosiran. EXPERT OPINION: The strong correlation and co-increase of homocysteine and methionine suggest that HHcy associated with givosiran is likely attributable to the impaired trans-sulfuration pathway catalyzed by cystathionine ß-synthase, which uses vitamin B6 as a cofactor. Data-based consensus supports monitoring total plasma homocysteine and vitamin B6, B12, and folate levels before and during givosiran treatment; supplementing with pyridoxine/vitamin B6 in patients with homocysteine levels >100 µmol/L; and involving patients with homocysteine levels >30 µmol/L in decisions to supplement.

Multiple roles of haem in cystathionine ß-synthase activity: implications for hemin and other therapies of acute hepatic porphyria.

The role of haem in the activity of cystathionine ß-synthase (CBS) is reviewed and a hypothesis postulating multiple effects of haem on enzyme activity under conditions of haem excess or deficiency is proposed, with implications for some therapies of acute hepatic porphyrias. CBS utilises both haem and pyridoxal 5'-phosphate (PLP) as cofactors. Although haem does not participate directly in the catalytic process, it is vital for PLP binding to the enzyme and potentially also for CBS stability. Haem deficiency can therefore undermine CBS activity by impairing PLP binding and facilitating CBS degradation. Excess haem can also impair CBS activity by inhibiting it via CO resulting from haem induction of haem oxygenase 1 (HO 1), and by induction of a functional vitamin B6 deficiency following activation of hepatic tryptophan 2,3-dioxygenase (TDO) and subsequent utilisation of PLP by enhanced kynurenine aminotransferase (KAT) and kynureninase (Kynase) activities. CBS inhibition results in accumulation of the cardiovascular risk factor homocysteine (Hcy) and evidence is emerging for plasma Hcy elevation in patients with acute hepatic porphyrias. Decreased CBS activity may also induce a proinflammatory state, inhibit expression of haem oxygenase and activate the extrahepatic kynurenine pathway (KP) thereby further contributing to the Hcy elevation. The hypothesis predicts likely changes in CBS activity and plasma Hcy levels in untreated hepatic porphyria patients and in those receiving hemin or certain gene-based therapies. In the present review, these aspects are discussed, means of testing the hypothesis in preclinical experimental settings and porphyric patients are suggested and potential nutritional and other therapies are proposed.

Development of siRNA Therapeutics for the Treatment of Liver Diseases.

Small interfering RNA (siRNA)-based therapeutics holds the promise to treat a wide range of human diseases that are currently incurable using conventional therapies. Most siRNA therapeutic efforts to date have focused on the treatment of liver diseases due to major breakthroughs in the development of efficient strategies for delivering siRNA drugs to the liver. Indeed, the development of lipid nanoparticle-formulated and GalNAc-conjugated siRNA therapeutics has resulted in recent FDA approvals of the first siRNA-based drugs, patisiran for the treatment of hereditary transthyretin amyloidosis and givosiran for the treatment of acute hepatic porphyria, respectively. Here, we describe the current strategies for delivering siRNA drugs to the liver and summarize recent advances in clinical development of siRNA therapeutics for the treatment of liver diseases.

Acute hepatic porphyrias: Current diagnosis & management.

Each of the four acute hepatic porphyrias is due to mutation of an enzyme in the heme biosynthetic pathway. The accumulation of pathway intermediates that occur most notably when these diseases are active is the basis for screening and establishing a biochemical diagnosis of these rare disorders. Measurement of enzyme activities and especially DNA testing also are important for diagnosis. Suspicion of the diagnosis and specific testing, particularly measurement of urinary porphobilinogen, are often delayed because the symptoms are nonspecific, even when severe. Urinary porphyrins are also measured, but their elevation is much less specific. If porphobilinogen is elevated, second line testing will establish the type of acute porphyria. DNA testing identifies the familial mutation and enables screening of family members. Management includes removal of triggering factors whenever possible. Intravenous hemin is the most effective treatment for acute attacks. Carbohydrate loading is sometimes used for mild attacks. Cyclic attacks, if frequent, can be prevented by a GnRH analogue. Frequent noncyclic attacks are sometime preventable by scheduled (e.g. weekly) hemin infusions. Long term complications may include chronic pain, renal impairment and liver cancer. Other treatments, including RNA interference, are under development.

Hepatocellular carcinoma in acute hepatic porphyrias: A Damocles Sword.

Porphyrias are inherited diseases with low penetrance affecting the heme biosynthesis pathway. Acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP) together constitute the acute hepatic porphyrias (AHP). These diseases have been identified as risk factors for primary liver cancers (PLC), mainly hepatocellular carcinoma (HCC: range 87-100%) but also cholangiocarcinoma, alone or combination with HCC. In AHP, HCC annual incidence rates range from 0.16 to 0.35% according to the populations studied. Annual incidence rates are higher in Swedish and Norwegian patients, due to a founder effect. It increases above age 50. The pathophysiology could include both direct toxic effects of heme precursors, particularly δ-aminolevulinic acid (ALA), compound heterozygosity for genes implied in heme biosynthesis pathway or the loss of oxidative stress homeostasis due to a relative lack of heme. The high HCC incidence justifies radiological surveillance in AHP patients above age 50. Efforts are made to find new biological non-invasive markers. In this respect, we describe here the first report of PIVKA-II clinical utility in the follow-up of an AIP patient that develop an HCC. In this manuscript we reviewed the epidemiology, the physiopathology, and the screening strategy of HCC in AHP.

Hepatic porphyria: A narrative review.

Porphyrias are a group of metabolic disorders, which result from a specific abnormality in one of the eight enzymes of the heme biosynthetic pathway. These have been subdivided based on the predominant site of enzyme defect into hepatic and erythropoietic types and based on clinical presentation into acute neurovisceral and cutaneous blistering porphyrias. This review focuses on hepatic porphyrias, which include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), aminolevulinic acid dehydratase deficiency porphyria (ADP), and porphyria cutanea tarda (PCT). Of these, AIP and ADP are classified as acute porphyria, PCT as cutaneous, while VP and HCP present with both acute and cutaneous clinical manifestations. Porphobilinogen levels in a spot urine sample is the initial screening test for the diagnosis of acute hepatic porphyria, and plasma with spot urine porphyrin levels is the initial screening test to approach patients suspected of cutaneous porphyria. Specific biochemical porphyrin profile for each porphyria helps in determining the specific diagnosis. Pain relief and elimination of triggering agents are the initial steps in managing a patient presenting with an acute attack. Intravenous glucose administration terminates the mild episode of acute porphyria, with intravenous hemin needed for management of moderate to severe episodes. Liver transplantation is curative and may be needed for patients with a life-threatening acute porphyria attack or for patients with recurrent acute attacks refractory to prophylactic treatment. Of the cutaneous porphyrias, PCT is the most common and is frequently associated with a combination of multiple susceptibility factors such as alcohol use, smoking, hepatitis C virus infection, HIV infection, estrogen use, and mutations of the hemochromatosis gene. Regular phlebotomy schedule and low-dose hydroxychloroquine are effective and safe treatment options for management of PCT.

[Hereditary coproporphyria from clinician's point of view--a case report].

INTRODUCTION: Acute hepatic porphyrias can mimic a range of unrelated diseases and conditions that may occur independently of porphyria and trigger their initial manifestations and further attacks. CASE REPORT: A 46-year-old female patient was subjected to cholecystectomy for biliary colic. Histopathological analysis revealed acute purulent exacerbation of chronic cholecystitis. On the 8th day post surgery, the patient was rehospitalized for nausea, abdominal pain, weakness and faintness, poor general condition, hypertension, tachycardia, apathy and profuse sweating. Laboratory findings revealed hyponatremia, hypokalemia, and metabolic alkalosis. Exploratory laparotomy did not detect a pathomorphological substrate. The patient was transferred to surgery department of the tertiary care institution. Due to metabolic imbalance, she was transferred to the Department of Endocrinology with signs of paleness, profuse sweating, tachycardia, and tachydyspnoea. The cardiologist performed echocardiography. The patient was diagnosed to have acute left ventricular failure and sub-acute myocardial infarction and transferred to the Department of Cardiology. Coronarography findings were normal. Cramps and pain in the legs with sensory loss, general weakness, apathy and mental confusion suggested acute hepatic porphyria. Thus, hereditary coproporphyria was diagnosed in the second month of illness. The treatment was continued at the Department of Gastroenterology. Clinical manifestations included polyneuropathy, flaccid paraparesis and acute brain syndrome, precordial oppressions and tachycardia. Haem arginate and hypertonic glucose were applied. The condition of the patient gradually improved. CONCLUSION: Porphyrias should always be taken into consideration in doubtful, frequently dramatic clinical pictures characterized by neurovisceral symptoms and precipitating factors of acute porphyria attacks must never be neglected.

The acute hepatic porphyrias: current status and future challenges.

The porphyrias are predominantly inherited metabolic disorders, which result from a specific deficiency of one of the eight enzymes along the pathway of haem biosynthesis. Historically, they have been classified into hepatic and erythropoietic forms, based on the primary site of expression of the prevailing dysfunctional enzyme. From a clinical point of view, however, it is more convenient to subdivide them into acute and non-acute porphyrias, thereby primarily considering the potential occurrence of life-threatening acute neurovisceral attacks. Unrecognised or untreated, such an acute porphyric attack is associated with a significant mortality of up to 10%. The acute hepatic porphyrias comprise acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and δ-aminolevulinic acid dehydratase deficiency porphyria. Making a precise diagnosis may be difficult because the different types of porphyrias may show overlapping clinical and biochemical characteristics. To date, the therapeutic possibilities are limited and mainly symptomatic. In this overview we report on what is currently known about pathogenesis, clinic, diagnostics, and therapy of the acute hepatic porphyrias. We further point out actual and future challenges in the management of these diseases.

Syndrome of inappropriate antidiuretic hormone secretion associated with coproporphyria: case report and review of literature.

OBJECTIVE: To remind physicians to consider the hepatic porphyrias in the differential diagnosis of the syndrome of inappropriate antidiuretic hormone secretion. METHODS: We present a case report of a patient seen in the hospital for severe hyponatremia, who was discovered to have the syndrome of inappropriate antidiuretic hormone secretion attributable to coproporphyria. Results of laboratory tests of the patient and her family are presented. RESULTS: A 54-year-old woman was seen in the hospital because of severe hyponatremia accompanied by generalized seizures. Her serum sodium concentration was 112 mEq/L, with concomitant serum and urine osmolalities of 235 and 639 mOsm/kg, respectively. Renal, thyroid, and adrenal functions were normal. Brain, chest, abdominal, and pelvic imaging studies were negative for occult malignant disease. Urinary excretions of porphobilinogen and aminolevulinic acid were substantially elevated. Results of follow-up urine, plasma, and fecal porphyrin studies were consistent with coproporphyria. Results of porphyrin metabolic studies of the patient's family showed normal findings in her parents and a minimally increased fecal coproporphyrin concentration and urinary uroporphyrin excretion in her sister. CONCLUSION: An endocrinology consultation is often requested for patients with hyponatremia. It is important to consider the acute hepatic porphyrias in the differential diagnosis, even though these are rare disorders and the family history may not always be helpful because of the high frequency of asymptomatic carriers.

Porfirias poco frecuentes: Casos detectados en la población argentina / Non frequent porphyrias in the argentinean population

Las porfirias son consecuencia de fallas en el metabolismo del hemo. Se clasifican según el tipo de sintomatología clínica prevalente o el órgano donde se expresa preferencialmente la falla metabólica. En general la deficiencia enzimática está asociada a mutaciones en los genes que codifican para cada una de las enzimas. Están descritos 7 tipos de porfiria diferentes. Se transmiten por carácter autosómico dominante a excepción de la PCE, la PHE y la NPA que son recesivas. Sin embargo, están reportadas variantes homocigotas para el resto de las porfirias de pronóstico y evolución mucho más grave que la forma heterocigota. La descripción de estos casos poco frecuentes, sus tratamientos y evolución, facilitarían tanto el diagnóstico diferencial de la porfiria como el conocimiento de las posibilidades terapéuticas en cada caso. Asimismo para las porfirias heterocigotas con manifestación infantil, su identificación temprana y tratamiento aseguraría una mejor evolución minimizando los riesgos asociados. Se han diagnosticado 5 casos de porfirias agudas en niñas: 2 de PAI, 2 de PV y 1 de CPH. Entre las porfirias cutáneas se presentan 25 casos de PCT infantil, el primer caso de PHE en Argentina, 4 casos de PCE infantil y 1 en un adulto y 2 casos de PPE con compromiso hepatobiliar.

The Porphyrias are a group of diseases resulting from partial deficiencies in one of the heme biosynthetic enzymes. These disorders can be classified on the basis of their clinical manifestations or according the organ where the metabolic deficiency is mainly expressed. In general this enzyme deficiency is associated with mutations in the genes which codify each enzyme. There are 7 types of Porphyrias. They are autosomal dominant disorders with the exception of PCE, PHE and NPA which are recessive. However, some rare and severe cases with recessive inheritance have also been reported. The description of these infrequent cases and their treatments and evolution would make easier the differential diagnosis of Porphyrias as well as the therapeutic possibilities to be applied in each case. Moreover, it is very important the early identification and treatment of infantile heterozygous porphyrias to avoid the risks of associatedd complications. In the CIPYP we have diagnosed 5 cases of infantil Acute Porphyrias: 2 PAI, 2 PV and 1 CPH. In the group of Cutaneous Porphyrias we present 25 cases of infantil PCT, the first case of PHE in Argentina, 4 cases of infantil PCE and 1 adult PCE and 2 cases of PPE with hepatic failure.

[Multifocal nodular fatty infiltration of the liver associated with porphyria and haemochromatosis]. / Multifokale noduläre Leberverfettung bei Porphyrie und Hämochromatose.

HISTORY AND CLINICAL FINDINGS: A 64-year-old woman suffered from severe fatigue. She was admitted to our outpatient unit for a diagnostic evaluation of multiple liver lesions as well as an adrenal gland tumor. Diabetes mellitus was diagnosed 22 years ago. Clinical evaluation revealed a mild obesity and a facial hypertrichosis. INVESTIGATIONS: Apart from elevated liver enzymes, serum ferritin and transferrin saturation were increased. Suspected haemochromatosis was verified by genetic analyses. Analyses of a 24 hours urine sample revealed typical constellation of a chronic hepatic porphyria. The liver lesions were diagnosed as multifocal fatty infiltrations using computer tomography. The patient refused a liver biopsy. The tumor of the adrenal gland represented an adenoma without endocrine activity. TREATMENT AND COURSE: Repeated phlebotomies were performed for the treatment of haemochromatosis. In the following serum ferritin returned to normal and liver enzymes as well as hyperporphyriuria decreased markedly. Diabetes was better controlled due to decrease of insulin requirements, too. CONCLUSION: This case report highlights the association of hereditary haemochromatosis and chronic hepatic porphyria, which presumably cause multifocal nodal fatty infiltration of the liver. Iron overload is likely the underlying cause, which represents the target for treatment options.

Porfiria variegata: signos cutáneos, agudos y bioquímicos. Primer estudio genético en pacientes Argentinos / Variegate porphyria: cutaneus sign, biochemistry and sharp. Genetic first study in Argentinean patients

Las porfirias son enfermedades metabólicas que surgen como consecuencia de una deficiencia enzimática parcial de alguna de las enzimas del hemo. En la porfiria Variegata (PV) este defecto se encuentra a nivel de la Protoporfirinógeno oxidasa (PPOX) quwe transforma el Protoporfirinógeno IX en Protoporfirina IX. Se caracteriza por presentar el síndromeagudo y cutáneo. Es una patología genéticamente heterogénea, al presente se han detectado 77 mutaciones diferentes en el gen de la PPOX, responsables de esta porfiria. Nuestro objetivo es el estudio bioquímico y molecular de pacientes con sintomatología de PV para llegar a un dignóstico certero de la enfermedad y hacerlo extensivo a sus familiares con el fin de identificar a los portadores asintomáticos y asesorarlos acerca del contacto con los factores desencadenantes de esta porfiria. Hasta el momento el estudio genético nos permitió detectar 2 mutaciones, una mutación puntual recientemente descripta que produce cambio de aminoácido, R168H en el exón 6 y una inserción nueva, 1320InT, que produce corrimiento del marco de lectura. Estos resultados han permitido confirmar el diagnóstico de PV en estos pacientes

[Hepatic porphyria]. / Les porphyries hépatiques.

INTRODUCTION: This review is aimed at presenting classification and diagnosis criteria of hepatic porphyrias and at proposing guidelines for diagnosis and management of these diseases. CURRENT KNOWLEDGE AND KEY POINTS: Porphyrias are inherited disorders: each type of porphyria is the result of a specific decrease in the activity of one of the enzymes of heme biosynthesis. Porphyrias are presently classified as erythropoietic or hepatic, depending on the primary organ in which excess production of porphyrins or precursors takes place. From 1970 to 1998, there have been important advances in the understanding of these diseases: specific enzyme deficiencies have been demonstrated, and genes have been isolated and located. These advances have been followed rapidly by identification of mutations. PERSPECTIVES AND PROJECTS: Treatment of acute attacks by hematin completely changed the disease prognosis. Relationships between porphyria cutanea tarda and hepatitis C virus or hemochromatosis have also been clarified. However, several important issues are still not solved: for instance, pathogenesis of neuronal dysfunction that produces the acute attacks is poorly understood. Differences related to susceptibility to develop acute attacks are not known.

Porfirias en la infancia: revisión casuística de 17 casos de niños con porfiria en un servicio de dermatología pediátrica manifestaciones cutáneas evaluación de características hereditarias propuesta terapéutica revisión bibliográfica / Porphyria of infancy: review of 17 cases from a pediatric dermatology service the cutaneous manifestations and hereditary characteristics

Entre agosto de 1987 y diciembre de 1996 se observaron en nuetros servicio de dermatolgía pediátrica, sobrre un total de 37.467 pacientes con consulta de primera vez, 17 niños con diagnóstico confirmado, con una prevalencia del 0,057 por ciento (1 caso de porfiria cada 2.000 consultas de primera vez). Los 17 casos se distribuyeron de la siguiente manera. Porfiria Cutánea Tarda (PCT): 9 casos (52,9 por ciento); Protoporfiria eritropoyética (PPE): 6 casos (35,3 por ciento); Porfiria Variegata (PV): 1 caso (5,9 por ciento) y Porfiria Eritropoyéctica Congénita de Günther (PCE): 1 caso (5, 9 por ciento). Relación: PCT/PPE: 1,5:1. La distribución de frecuencia acorde a sexo y edad fue la siguiente: PCT: relación F/M: 2:1 (F= 6 casos; M= 3 casos); Edad: Rango= 3 a 12 años X= 7 años. PPE: relación F/M: 1:2 (F= 2 casos; M= 4 casos); Edad: Rango= 2 a 11 años X= 7 años. PV: 1 caso de una niña de 8 años. PEC: 1 caso de una niña de 2 meses. El diagnóstico de porfirinas en orina, plasma, eritrocitos y materia fecal y el índice de fluorescencia plasmática, acorde a su correlación clínica. Se evaluaron los antecedentes hereditarios en la mayoria de los pacientes, observándose diferentes cuadros de porfiria comprobados en los familiares, fundamentalmente en los niños portadors de PCT. Los síntomas iniciales estuvieron asociados con fenómenos de fotosensibilidad y aparición de lesiones vesico-ampollares en regiones expuetas, principalmente cara y dorso de manos. La hipertricosis fue constante en los casos de PCT. Hubo compromiso abdominal en los casos de PEC y PV y severa onicodistrofia con hipertricosis, anemia hemolítica y mal estado general en el caso de Günther. Un caso de PCT asociado con leucemia mieloide y otro en un paciente post-transplantado renal (no diálisis). En todos los pacientes con PPE se realizaron biopsias hepáticas con resultados normales...

Coproporfiria hereditaria. Estudios bioquímicos en 7 pacientes sintomáticos y familiares / Coproporphyria heredity. Studies biochemistry in 7 patients sintomatics and familiaries

Se han estudiado 7 pacientes con coproporfiria herediatria (CPH) sintomática: en 6 de ellos se investigaron 14 familiares consanguíneos. Tres de los siete (43 por ciento) pacientes exhibián signos cutáneos hiperpigmentación, fotosensibilidad, y/o máculas y todos presentaron ataques neuroviscerales. Desde el punto de vista bioquímico los pacientes excretaban niveles elevados de precursores y/o porfirinas en orina ácido 5-aminoleválico (ALA) (3,9 - 14,1 mg/24h), porfobilinógeno (PBG) (6,5 - 47,9 mg/24h), porfirinas totales (645-31129 mug/24h), que disminuyeron alcanzada la remisión (ALA: 0,2 - 5,3 mg/24h: PBG: 0,8 -25,2 mg/25,2 mg/24h, porfirinas totales 112-952 mu/24h, valor normal: ALA 2-4 mg/24h: PBG: 1-2 mg/24h. Porfirinas 20-250 mug/24h). Las profirinas fecales también estuvieron incrementadas la fase aguda (316-50.056 mug/g seco) y en remisión (165-1600) mug/g seco) valor normal <= 130 mu/g seco. El patrón de excreción de porfirinas urinarias y fecales mostró siempre una elevada concentración de coproporfirinas, la longitud de onda de emisión (618 nm) de las porfirinas plasmáticas permitió identificar la porfiria como una CPH y distinguirla de la porfiria variegata (PV). El tratamiento del ataque agudo de la CPH fue semejante al empleado en los casos de porfiria aguda intermitente o PV carbohidratos (ataques agudos 300- 500 g/diarios, ataques leves 20 - 40 g/diarios) complejo vitamínico B y ácido fólico (30 mg/día). Cuando los pacientes presentaron signos clínicos cutáneos se administró S-adenosil-L-metionina 12 mg/kg/día durante 3 semanas.