Acute Hepatic Porphyria (Porphyria due to ALA dehydratase deficiency)

Acute hepatic porphyria is a term encompassing four types of porphyria, in which the production of toxic heme precursors occurs in the liver and causes acute attacks of abdominal pain, nausea, neurological and mental changes, as well as hypertension and pain in the head and neck and/or chest. The diagnosis is made by detecting specific heme precursors in urine or feces. Hematin, symptomatic therapy and liver transplantation are used as therapy.

Presentation

The clinical presentation is quite similar across all types of acute hepatic porphyrias. The "acute attacks" are the hallmark of these disorders, most frequently encountered after puberty in women [5]. Most important symptoms are related to the gastrointestinal tract and include intense and nonspecific abdominal pain that may be cramping, constipation, nausea, vomiting, decreased bowel sounds and diarrhea in some patients [1] [3] [5]. Head, neck and chest pain are seen in approximately 50% of cases, as are hypertension, tachycardia, mental changes (restlessness, anxiety, insomnia, disorientation, paranoia and hallucinations) and convulsions [1] [9]. Muscle weakness, tremor, diaphoresis, dysuria, dark urine, bladder distension and severe neuropathy may be encountered as well [5], and a missed diagnosis may lead to severe and irreversible motor neuropathy [2]. In addition to acute attacks, some forms may be accompanied by cutaneous symptoms, such as HCP, in which photosensitivity and blistering skin lesions (vesicles, bullae and erosions with scarring) are constitutive features [1] [5].

Workup

To make the diagnosis of acute hepatic porphyrias, a thorough patient history that will reveal presence of any of the mentioned porphyrias (having in mind the autosomal dominant pattern of inheritance), recent use of drugs or habits that may have precipitated the attacks, as well as history of similar symptoms, is essential. Together with a thorough physical examination, sufficient information can be gathered to suspect porphyria as an underlying cause. To confirm the diagnosis, urine and fecal testing for heme precursors and toxic metabolites should be performed. A distinction between subtypes can be made based on the obtained findings. AIP is suspected when markedly higher levels (20-100x higher) of ALA, PBG and uroporphyrin are found in urine, whereas detection of high coproporphyrin III levels in urine and stool, in addition to ALA and PBG in urine, is highly specific for HCP [5]. VP, on the other hand, is distinguished from HCP by confirming the presence of protoporphyrin in stool [5]. Urine and stool samples should be obtain during or right after the acute attacks [2]. A definite diagnosis is made through genetic tests, specifically polymerase chain reaction (PCR), which will detect the exact type of mutation [1].

Treatment

Initial therapeutic measures of acute hepatic porphyrias are focused on symptom alleviation - management of tachycardia, electrolyte dysbalance (hyponatremia is common, and often the cause of seizures) and gastrointestinal irritation [8]. Phenytoin or valproic acid should be avoided in management of seizures, as they may cause more severe symptoms [2]. Instead, benzodiazepines, gabapentin, magnesium and propofol (in the setting of refractory seizures) are used. Intravenous administration of hemin (a synthetic form of heme), however, is the mainstay of treatment, especially when dealing with acute attacks [2] [10]. Hemin is able to expand the pool of heme in hepatocytes, which produces a negative feedback mechanism that will reduce the production of heme precursors, most notably ALA [2]. Intravenous infusions will lead to resolution of symptoms within 3-4 days, and the lipophilic form (hematin), or heme arginate, is given in doses of 3 mg/kg per 24 hours as a single dose for 4 days [9]. For more severe enzyme deficiencies that cause recurrent life-threatening attacks and predispose patients to progressive motor neuropathies, liver transplantation may be indicated, but proper follow-up and rigorous anticoagulant therapy is mandatory, since a very high risk for hepatic artery thrombosis has been noted [9].

Prognosis

Before the introduction of modern critical care and directed therapy, mortality rates exceeded 35%, but with early identification and increased awareness of the disorder, patients achieve a good prognosis through long-term monitoring and avoidance of factors that are known to induce acute attacks [2]. However, numerous complications may arise, especially if the diagnosis is made late, most important being irreversible nerve degeneration (characteristic for AIP), renal insufficiency, chronic hypertension and hepatocellular carcinoma, which seems to be age-related and more commonly encountered among patients suffering from ongoing liver disease [2] [6].

Etiology

Acute hepatic porphyrias are all caused by genetic deficiencies of enzymes involved in one of the steps of heme synthesis, many of which occur in the liver. Although only 15% of total heme is synthesized in the liver, genetic mutations reduce enzymatic activity by 50% in AIP, HCP and VP, whereas 95% reduction is seen in ADP [5]. Apart from an autosomal recessive pattern of inheritance seen in ADP, all hepatic porphyrias are caused by autosomal dominant mutations, leading to accumulation of neurotoxic substances in the liver, presumably γ-aminobutyric acid analogs and/or porphobilinogen (PBG) [5].

Epidemiology

Prevalence rates of acute hepatic porphyrias significantly vary across different types and geographical regions. Overall prevalence rate of AIP in Europe is estimated at 1 in 75,000 individuals, ranging from 1 in 1,000 in northern Sweden to 2 in 100,000 in Finland, while Argentina reports rates of 1 in 125,000 individuals [1]. On the other hand, valegriate porphyria (VP) is most commonly encountered in South Africa, where 1 in 300 individuals suffer from this type of porphyria due to founder effect [6]. Other countries report much lower rates (2 per 100,000 in Finland and 1 per 600,000 in Argentina) [1]. Up to 2015, only 6 cases of ADP are reported [6]. Numerous precipitating factors or events are well-established inducers of acute attacks: lipophilic drugs (rifampicin, sulfonamide antibiotics, barbiturates and hydantoins) [6], corticosteroids, androgens, alcohol, organic solvents, pesticides, but also profound emotional stress, caloric deprivation that leads to severe fasting and physical effort [1] [6]. It must be noted that some types of hepatic porphyria, such as AIP, are more prevalent among women [6].

Sex distribution
Age distribution

Pathophysiology

Heme formation is a complex metabolic pathway involving eight different enzymes, all being potential targets for genetic mutations and the occurrence of porphyrias [7]. 85% of heme is formed in erythrocytes, and only 15% in the liver, but about 80% of heme synthesized in this organ is necessary for activity of cytochromal P450 enzymes and the electron transport chain in the TCA cycle, which are essential for degradation of toxic chemical and energy formation, respectively [1]. In the setting of genetic mutations that cause deficiencies of enzymes involved in heme synthesis, the pathogenesis of porphyrias stems from insufficient heme production and consequent hepatic accumulation of its precursors, in the attempt to accelerate the production of heme. As enzyme deficiencies impair the ability of the liver to produce heme, these precursors accumulate and become toxic (presumably γ-aminobutyric acid analogs, ALA, and/or porphobilinogen) and their deleterious effects develop through interaction with γ-aminobutyric acid (GABA) or glutamate receptors, the sites where main neuronal transmitters exert their effects [2] [5]. For symptoms to appear, however, the accumulation of these metabolites is not sufficient, but intake of certain drugs, stress, or severe caloric deprivation causes further saturation of cytochromal enzymes and even larger accumulation of toxic metabolites, eventually breaching the threshold of tolerance by the body resulting in the onset of symptoms.

Prevention

Genetic counselling may be highly recommended for families with a positive history for porphyrias. For those in whom the diagnosis is confirmed, several preventive measures may be of significant benefit [2] [8]:

  • Avoiding use of hazardous drugs and exposure to substances that are known inducers of acute attacks.
  • Avoid periods of starvation and profound fasting.
  • Prophylactic therapy with hematin.
  • Regular screening - Abdominal ultrasonography and serum alpha-fetoprotein levels performed on an annual basis after 50 years of age is recommended, primarily to identify early signs of liver disease and hepatocellular carcinoma.

Summary

Porphyrias are a group of genetic disorders that arise as a result of deficiency of enzymes involved in the formation of heme, a vital constituent of hemoglobin and cytochromal enzymes that participate in metabolism of numerous drugs in the liver and in the tricyclic acid cycle (TCA), where they are necessary cofactors in the electron transport chain [1]. Based on the onset of symptoms, porphyrias are generally divided into acute and non-acute, and a further classification according to the type of symptoms (neurovisceral and/or cutaneous) can be made as well [1] [2]. Additionally, porphyrias can be classified into hepatic and erythropoietic, depending the site of overproduction of toxic metabolites [3], and four hepatic porphyrias are recognized in literature [4] [5] [6]:

  • δ-aminolevulinic acid dehydratase deficiency (ADP) porphyria - Only a six cases of ADP have been described in literature up to today, in which the second step of heme synthesis (condensation of two molecules of δ-aminolevulinic acid - ALA into porphobilinogen) is affected by autosomal recessive mutations [2].
  • Acute intermittent porphyria (AIP) - Considered as one of the most common forms of porphyria, AIP is inherited through autosomal dominant patterns, and is caused by mutations in hydroxymethylbilane synthase (HMB-synthase) gene, responsible for the third step of heme synthesis - conversion of porphobilinogen (PBG) into uroporphyrinogen [2]. The clinical presentation appears in only 10% of mutation carriers and comprises typical acute attack consisting of nonspecific abdominal pain, nausea, tachycardia, vomiting, constipation, mental changes, convulsions, hypertension and pain in the head, neck and/or thorax [1].
  • Hereditary coproporphyria (HCP) - Deficiency of coproporphyrinogen oxidase (CPOX), necessary for the sixth step of heme formation - conversion of coproporphyrinogen III to protoporphyrinogen IX, through autosomal dominant mutations of the CPOX gene is the mechanism of disease in this type of porphyria [1]. The majority of patients exhibit acute attacks, while 20% can also present with skin-related symptoms, such as photosensitivity and blistering skin lesions [1].
  • Variegate porphyria (VP) - Like AIP and HCP, variegate porphyria (VP) is inherited by autosomal dominant transfer of mutated genes that code for protoporphyrinogen oxidase (PPOX), which is necessary for the conversion of protoporphyrinogen to protoporphyrin, the seventh and second-last step in heme synthesis [6]. Adult-onset of cutaneous blistering lesions (subepidermal vesicles, erosions, bullae) of the sun-exposed skin and acute attacks of abdominal and chest pain, constipation, muscle weakness that can be severe enough to cause paralysis of the limbs and respiratory muscles, as well as psychiatric disturbances are main symptoms of VP [7].

Two main features are shared by all porphyrias. Firstly, the onset of symptoms stems from accumulation of toxic substances of the heme pathway due to enzyme deficiencies; and secondly, these metabolites are not sufficient by themselves to cause symptoms [4]. Acute attacks are precipitated by various factors and events, including alcohol, pesticides, organic solvents, caloric deficiency, corticosteroids, and numerous lipophilic drugs (barbiturates, rifampicin, sulfonamide antimicrobials etc.) [1] [6]. For this reason, the diagnosis of hepatic porphyrias can be made by detecting heme precursor metabolites in urine or feces after use of certain drugs, substances or nutritional-related effects. Treatment principles comprise discontinuation of potentially hazardous drugs, administration of hematin (a synthetic form of heme that inhibits production of toxic metabolites), dextrose, symptomatic care, and in most severe cases, liver transplantation [8].

Patient Information

Porphyrias are a group of inherited disorders that cause insufficient formation of heme, a precursor of hemoglobin and a vital constituent of various liver enzymes involved in metabolism of numerous drugs and toxic substances. Based on their clinical features and site of occurrence, they can be divided into acute or non-acute, hepatic or erythropoietic (originating from the liver or red blood cells, respectively) and neurovisceral or cutaneous, implying that symptoms may be related either to the nervous system and internal organs or the skin. Acute hepatic porphyrias are a group of disorders in which enzyme deficiencies cause insufficient formation of heme in the liver and subsequent accumulation of toxic metabolites of this pathway in the same organ. Delta-aminolevulinic acid dehydratase deficiency (ADP) porphyria, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP) are representatives of this group. For symptoms to appear, enzyme deficiencies are not sufficient by themselves, but additional factors are necessary to trigger their onset. Examples are use of drugs metabolized by enzymes that use heme as its substrate, such as rifampicin, barbiturates, and sulfonamide antibiotics, whereas corticosteroids and androgens, profound fasting due to starvation, emotional stress, exposure to organic solvents, pesticides, and alcohol are other notable examples. The hallmark of hepatic porphyrias are "acute attacks" of nonspecific and intense abdominal pain accompanied by nausea, vomiting, cramping, constipation and deceased bowel sounds, hence the term acute hepatic porphyria. Additional signs include head, neck and chest pain, hypertension, seizures, mental changes (restlessness, anxiety, confusion, insomnia, disorientation), and neuropathies that can induce severe muscle weakness. The diagnosis can be made by detecting toxic metabolites in urine or feces and genetic testing may be performed as a confirmation. Treatment initially focuses on alleviation of symptoms through stabilizing blood pressure and seizures, as well as gastrointestinal complaints. The mainstay of therapy, however, is administration of synthetic heme (known as hematin or heme arginate), which increases the pool of heme in the liver, thus reducing the production of toxic metabolites. Because acute attacks may be recurrent and severe, and even life-threatening, liver transplantation may be considered. For the same reason, a late diagnosis is detrimental, as current therapeutic modalities and preventive strategies (avoiding use of drugs or other factors that can precipitate the onset of symptoms) can successfully treat the condition and prevent long-term sequelae.

Self-assessment

References

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