Abstract:

Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death. Porphyric neuropathy is an acute to subacute motor predominant axonal neuropathy with a predilection for the upper extremities and usually preceded by a predominantly parasympathetic autonomic neuropathy. The rapid progression and associated dysautonomia mimic Guillain-Barré syndrome but are distinguished by the absence of cerebrospinal fluid albuminocytologic dissociation, progression beyond 4 wk, and associated abdominal pain. Spot urine test to assess the porphyrin precursors delta-aminolevulinic acid and porphobilinogen can provide a timely diagnosis during an acute attack. Timely treatment with intravenous heme, carbohydrate loading, and avoidance of porphyrinogenic medications can prevent further neurological morbidity and mortality.

Introduction

Porphyrias are inherited metabolic disorders due to mutations in the genes encoding for the eight enzymes in the heme biosynthetic pathway, resulting in partial enzyme deficiencies and overproduction of heme precursors. Heme, the final product of the heme biosynthetic pathway, is biologically important, while upstream intermediates, porphyrins and their precursors, are non-functional and potentially neurotoxic. 

Biochemically, porphyrias are classified as hepatic or erythropoietic, depending on major sites of production of heme precursors. Clinically, porphyrias are categorized as acute neurovisceral or cutaneous porphyrias based on the primary expression of symptoms. Hepatic porphyrias are further classified into acute and chronic based on genetic defects and clinical presentations.

Acute hepatic porphyrias (AHP) include acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and delta-aminolevulinic acid dehydratase (ALAD) deficiency porphyria (ADP) which present with neurological manifestations predominantly although HCP and VP can have photo-cutaneous lesions as well. Chronic hepatic porphyrias and erythropoietic porphyrias primarily present with photo-cutaneous lesions that will not be discussed in this review paper.

Porphyric neuropathy is one of the disabling and potentially fatal clinical manifestations of acute hepatic porphyria (AHP). The clinical manifestations of porphyric neuropathy may vary widely from focal neuropathy to an acute, severe motor predominant polyneuropathy with quadriparesis mimicking Guillain-Barre syndrome (GBS). An understanding of porphyric neuropathy and manifestations of AHP, along with a high index of suspicion, and appropriate tests are required to assist in the early diagnosis and proper management of the AHPs

Pathogenesis

Most heterozygous AHPs have 50% reduced enzyme activity, which is adequate to supply hepatic heme to maintain normal functional status, but the surge of sex steroids caused by puberty, alcohol, smoking, starvation, and porphyrinogenic drugs increase heme demands and lead to upregulation of the rate limiting enzyme aminolevulinic acid synthase-1 (ALAS-1) and production of the neurotoxic heme precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) in some AHP patients. Several theories have been proposed to explain the pathophysiology behind neurological symptoms of AHP. Presently, heme deficiency and direct ALA neurotoxicity are the leading explanations for neuronal dysfunction. These may not be mutually exclusive and likely differ between affected cell types of the central and peripheral nervous systems.

Heme deficiency:  Heme deficiency can lead to reduced production of key hemoproteins, such as mitochondrial, microsomal, and other cytochromes, nitric oxide synthase, and tryptophan dioxygenase resulting in direct or indirect effects on the nervous system. Resolution of an acute attack with intravenous (IV) heme therapy supports this theory but it is unclear how IV heme also reverses central nervous system (CNS) manifestations when it cannot cross the blood–brain barrier.

Heme deficiency leading to reduced mitochondrial cytochromes and other important hemoproteins required for the electron transport chain may lead to impaired oxidative phosphorylation and reduced ATP production in neurons and glial cells, impaired Na+/K+ pump function for axonal transport, and impairment of other ATP mediated signaling in the nervous system, which may contribute to porphyric neuropathy. Demonstration of disordered mitochondrial function in AHP mouse models and symptomatic AHP subjects supports this theory.

Nerve excitability studies have demonstrated deficits in inward rectifying current and impaired depolarization during visceral attacks without neuropathy, which suggests subclinical hypoxia and impaired cellular metabolism. As neuropathy ensues, excitability studies show elevated thresholds for generating an action potential, consistent with axonal membrane depolarization implicating impaired Na+/K+ pump function as being involved in the pathogenesis of the porphyric neuropathy. Energy requirements of cells depend on multiple factors, such as the size and number of ion channels. Motor neurons have large soma, and long axons resulting in higher demands on axonal transport, which may explain predominant motor involvement.

Reduced levels of activity of tryptophan dioxygenase may lead to increased levels of tryptophan with resultant increased serotonin production. Increased excretion of tryptophan metabolites has been demonstrated in patients with acute porphyria, ameliorated by heme infusions, which supports this theory. Serotonin has been associated with mood disorders, emesis, peristaltic reflex, tachycardia, systemic arterial hypertension, altered cholinergic transmission in the urinary bladder, and nociceptive effects. Thus, increased levels of serotonin may contribute to the autonomic and behavioral symptoms of AHP.

Reduced activity of nitric oxide synthase, another heme containing enzyme, may lead to reduced nitric oxide, which may also lead to visceral symptoms, pain, and tachycardia, and hypertension secondary to effects on vasculature.

Porphyria

• Group of inherited disorders caused by heme synthesis

• 3 forms of porphyria that are associated with peripheral neuropathy as wells as CNS abnormalities:

  • AIP

  • HCP

  • VP

• Other forms of porphyria including X-linded sideroblastic anemia, ALAD-deficient porphyria, congenital erythropoietic porphyria, erythropoietic porphyria, except porphyria cutanea tarda have the potential to result in a neuropathy.

Porphyria are a group of metabolic disorders arising from a defect in the heme biosynthetic pathway.  Clnical presentation is diverse and neuropathies, and an acute intermittent porphyria (AIP).   AIP is an autosomal dominant disease due to deficiency of hydroxmethylbilane synthase (encoded by HMBS gene).  Most, if not at all, peripheral neuropathy is described have concomitant involvement of the large nerve fibers, suggesting that he does not appear SFN.  However, autonomic neuropathy was responsible for variety of symptoms during the acute attack and the majority of patients with AIP.  Manifest with autonomic dysfunction without large fiber peripheral neuropathy or focal CNS impairment.

Clinical features:  The acute neurological features are similar, however, a photosensitive rash is seen with HCP and VP but not seen in AIP.  Attacks of porphyria can be triggered by certain drugs (usually those metabolized by the P450 system), hormonal changes (pregnancy, and luteal phase of the menstrual cycle), and dietary restrictions. 

An acute attack of porphyria is often heralded by acute abdominal pain.  Later patients may develop agitation, hallucinations, or seizures.  Several day later, back and leg pain followed by weakness can occur and may mimic GBS.  Motor involvement is usually asymmetric, proximal, or distal and affects arms or leg preferentially.  CN are also affected, leading to facial weakness and dysphagia. Sensory impairment may be difficult to determine if the patient is encephalopathic.  Muscle stretch reflexes are often reduced.  Autonomic dysfunction manifested by signs of sympathetic overactivity (pupillary dilatation, tachycardia, and HTN) is common.  Constipation, urinary retention, and incontinence can also be seen.  Recovery is usually good, provided treatment is instituted rapidly to prevent excessive amounts of axonal damage. 

Laboratory features: 

• CSF protein is normal or mildly elevated.

• LFTs and hematology are usually normal.

• Some patients are hyponatremic (SIADH).

• Hoesch test:  Urine may appear brownish in color secondary to high concentrations of porphyrin metabolites.

• Laboratory Diagnosis of Porphyria - PMC 

• Urine and stool are checked for accumulating intermediary precursor of heme:

  • delta-aminulevulinic acid - ALAD deficient porphyria

  • prophobilinogen - AIP

  • uroporphobilinogen

  • coproporphyrinogen - HCP

  • protoporphyrinogen - VP

• The specific lowered enzyme activities can be also measure in erythrocytes and leukocytes.

• EDX:

  • Sensory NCS usually demonstrate normal NCV and DL but amplitudes may be slightly reduced though not to the same degree as CMAPs are reduced.

  • Motor NCV are mildly reduced or normal and DL are normal or slightly prolonged. 

  • The primary abnormality on NCS is the marked reduction of CMAP amplitudes.

  • nEMG demonstrates primarily a reduced recruitment, fibrillation potentials, and positive sharp waves. 

• Histopathology:

  • Axonal degeneration in apparent nerve biopsies. 

• Molecular Genetics and Pathogenesis:

  • Porphyrias are AD.

  • AIP is associated with porphobilinogen deaminase deficiency

  • HCP is caused by defects in coproporphyrin oxidase

  • VP is associated with protoporphyrinogen oxidase

  • AIP the most common acute hepatic porphyrias.  It is caused by a mutation in hydroxymethylbilane synthase, the second step in the pathway that produces heme.  Lack of heme induces upregulation of the first enzyme of the first enzyme in the pathway, ALS synthase 1 (ALAS1), in an attempt to ramp up heme production.  The futile overactivity of ALSA1 leads to a buildup of two upstream intermediates including delta-aminolevulinic acid (ALA), which is believed to be the most important neurotoxic species.  Clinical symptoms of AIP include a motor-predominant neuropathy, arrhythmia, and intense abdominal pain, likely from bowel stasis.  The inability to detoxify various drugs in the liver may have secondary toxic effects on the nervous system.  

• Treatment:

  • IV glucose started at a rate of 10-20 g/h.  If there is no improvement in 24 hours, then IV hematin at 2-5 mg/kg/d for 3-14 days should be given.

  • Hematin dose can be infused over a 30-60 minute period.

  • Avoid drugs that can precipitate the acute porphyric attack.

    • Avoid barbiturates

  • Givosiran interfering RNA binds to the messenger RNA of ALAS1, triggering its degradation by the cellular defense machinery, reducing enzyme production and thus ALA build-up.  

  • GIVLAARI® (givosiran) | HCP 

About the APF - American Porphyria Foundation