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Acute Porphyrias and Porphyric Neuropathy.Indd REVIEW Acute porphyrias and porphyric neuropathy Doungporn Ruthirago MD, Parunyou Julayanont MD, Supannee Rassameehiran MD ABSTRACT The porphyrias are a group of uncommon inherited metabolic disorders of heme biosynthesis. Acute porphyrias are specific types of porphyrias characterized by the presence of acute attacks that usually present with abdominal pain, psychiatric symp- toms, and neuropathy. The nonspecific porphyria presentations, the complexity of heme biosynthesis, and difficulty in interpreting the laboratory tests make the diagnosis of por- phyria challenging. Treatment of acute porphyria and avoidance of precipitating factors should be initiated early to prevent potentially severe long-term sequelae from nerve dam- age. Porphyric neuropathy is one such complication and is characterized by an axonal neuropathy with predominant motor involvement. Sensory neuropathy is also found but is less common. Although the exact pathophysiology of porphyric neuropathy remains uncertain, neural energy failure from heme deficiency and neurotoxicity from porphyrin precursors are probably the two main mechanisms. The understanding of porphyric neu- ropathy and manifestations of each type of porphyria along with timely implementation of appropriate tests can significantly assist in the diagnosis of these rare diseases. Key words: porphyria; porphyric neuropathy; neuropathy; nervous system; heme INTRODUCTION The porphyrias are groups of uncommon dis- and psychiatric manifestations.1 Each presentation is eases occurring secondary to an autosomal dominant nonspecific, mimicking other diseases that are much inherited deficiency of enzymes in the heme biosyn- more common and making the diagnosis of porphyr- thetic pathway. Each porphyria is caused by a differ- ias challenging. A high index of suspicion and appro- ent enzymatic alteration that leads to accumulation of priate laboratory investigation at the proper time are heme precursors, causing various clinical symptoms. essential to establish the diagnosis. Porphyrias have a high degree of symptom variance, including gastrointestinal, neurological, cutaneous, Porphyrias can be broadly categorized into acute porphyrias and non-acute porphyrias depend- ing on the presence of acute porphyric attacks. Pa- tients who present with acute attacks need more ur- Corresponding author: Doungporn Ruthirago , MD gent diagnosis and treatment to prevent potentially Contact Information: [email protected] severe long-term sequelae. The well-known triad of DOI: 10.12746/swrccc2016.0415.197 The Southwest Respiratory and Critical Care Chronicles 2016;4(15) 21 Doungporn Ruthirago,et al Acute porphyrias and porphyric neuropathy abdominal pain, neuropathy,and psychiatric distur- coproporphyrinogen oxidase (CPOX) enzyme to pro- bances helps the clinician recognize acute porphyr- toporphyrinogen. Protoporphyrinogen is changed into ias.2 However, in many cases patients present with protoporphyrin IX by protoporphyrinogen oxidase only one or two symptoms. Sensory or motor neu- (PPOX). The last step of synthesis is adding iron to ropathy may be the most objective clinical manifesta- protoporphyrin IX by the ferrochelatase (FECH) en- tion that assists in the diagnosis of these uncommon zyme to form heme (Table).7 diseases. Comprehensive reviews of the porphyrias 3, 4 are currently available in other literatures. The ob- Enzymatic defects in each step of the heme jective of this article is to simplify the understanding of biosynthetic pathway cause susceptibility to different the acute porphyrias and porphyric neuropathy. types of porphyria. The specific deficiency predicts which heme precursors or intermediates will accumu- The word “ porphyria” is derived from the late and later be excreted in the feces or urine. These Greek word “ porphura” which means purple.5 This excess metabolites are sometimes oxidized into pig- is from the observation that the urine of porphyria mented porphyrins and produce red/purple urine.1 patients has a red-purple color and becomes darker Environmental factors also have an important role in when exposed to light. Due to their enzymatic defi- development of acute porphyrias. Acute attacks occur ciency these patients have excess porphyrins and from events that induce ALAS directly or increase the porphyrin precursors which accumulate in the body requirements of heme synthesis which indirectly dis- and are later excreted into urine and feces.6 inhibit ALAS.8 For example, porphyrinogenic drugs, such as barbiturates and sulfa antibiotics, induce PATHOPHYSIOLOGY cytochrome P450, causing increased hepatic heme turnover. Infection and inflammation induce the ex- HEME BIOSYNTHESIS pression of hepatic acute phase protein that catabo- lizes heme.3 Transcription of ALAS is stimulated by Heme is an oxygen carrier which is important peroxisome proliferator-activated receptor gamma to all aerobic reactions. It also functions as a source of coactivator 1-alpha (PGC-1α), which involves energy electrons in the mitochondrial electron transport chain. metabolism and explains why acute porphyria is pre- 9 Heme is synthesized in the bone marrow and liver and cipitated by starvation. is required for the synthesis of hemoproteins-hemo- globin, myoglobin, and cytochromes, etc. Heme syn- PATHOPHYSIOLOGY OF PORPHYRIC NEUROpaTHY thesis starts in the mitochondria where succinyl coen- zyme A combines with glycine to form aminolevulinic Every symptom of acute porphyrias can be acid (ALA). This process is catalyzed by aminolevu- explained by dysfunction of the nervous system.3 Ab- linic acid synthase (ALAS) which is the rate-limiting dominal pain during acute attacks reflects autonomic step of heme synthesis. Aminolevulinic acid synthase neuropathy that causes ileus, abdominal distension, is inhibited by heme in a negative feedback pathway. followed by pain, constipation, nausea, and vomiting. When the requirement for heme increases or the Psychiatric disturbances can be explained by central reserves are depleted, ALAS is disinhibited and the nervous system involvement. Acute porphyric neuro- heme metabolic pathway is activated. The next steps visceral attacks develop in genetic-susceptible indi- occur in the cytoplasm where two ALAs are converted viduals when environmental triggers activate ALAS1, to porphobilinogen (PBG) by aminolevulinic acid de- making deficient enzymes in later steps of heme bio- hydratase (ALAD). Four PBGs are combined to form synthesis become the rate-limiting step, leading to uroporphyrinogen by uroporphyrinogen cosynthase accumulation of porphyrin precursors, such as ALA (UROS) enzyme. Uroporphyrinogen is later changed and PBG.10 to coproporphyrinogen by the uroporphyrinogen de- carboxylase (UROD) enzyme. Coproporphyrinogen Porphyric neuropathy may be explained by enters the mitochondria where it is converted by the 2 mechanisms.10 The first mechanism is direct neu- 22 The Southwest Respiratory and Critical Care Chronicles 2016;4(15) Doungporn Ruthirago,et al Acute porphyriasandporphyricneuropathy DoungpornRuthirago,etal Table Clinical presentation Laboratory findings (increased level) Mode of Neuro- Enzymatic defects Genes Diseases Cutaneous inheritance visceral Urine Feces Plasma Erythrocyte Mito- involvement involvement chon- Glycine + Succinyl CoA X-linked dominant dria ALA synthase ALA synthase gene protoporphyria X-linked Free and Zn No Yes NA Protoporphyrin Protoporphyrin dominant protoporphyrin (increased enzyme) (gain of function) (XLP) ALA dehydratase ALA, Delta-Aminolevulinic acid ALA dehydratase Zn protopor- ALA dehydratase deficiency por- AR Yes No NA NA gene phyrin phyria (ADP) Coproporphyrin III Acute intermittent Porphobilinogen, Uroporphyrin Uroporphyrin Porphobilinogen Porphobilinogen Porphobilinogen porphyria Uroporphyrin AD Yes No deaminase deaminase gene (AIP) ALA, (sometimes) (sometimes) (sometimes) Uroporphyrin Hydroxymethylbilane Cyto- Congenital eryth- Uroporphyrin I, Uroporphyrin, Uroporphyrinogen Uroporphyrinogen Uroporphyrin I, ropoietic porphyria AR No Yes Coproporphyrin I plasm III cosynthase III cosynthase gene Coproporphyrin I (CEP) Coproporphyrin I Coproporphyrin Uroporphyrinogen III Hepatoerythro- Uroporphyrin III, Isocoproporphy- Uroporphyrin, Uroporphyrinogen Uroporphyrinogen poietic porphyria rin, Heptacar- ± Zn protopor- AR No Yes Uroporphyrinogen I decarboxylase decarboxylase gene boxyl porphyrin, phyrin IX I Heptacarboxyl Coproporphyrin I Heptacarboxyl (HEP) porphyrin porphyrin Familial porphyria Coproporphyrinogen I Uroporphyrin, Isocoproporphy- Uroporphyrin, Uroporphyrinogen Uroporphyrinogen cutanea tarda AD No Yes rin, Heptacarbox- NA decarboxylase decarboxylase gene Heptacarboxyl yl porphyrin Heptacarboxyl (fPCT) Coproporphyrinogen porphyrin porphyrin Hereditary copro- Coproporphy- Coproporphyrin III, porphyria rin III, Coproporphyrinogen Coproporphyrinogen Coproporphyrin Coproporphyrin AD Yes Yes NA oxidase oxidase gene (HCP) Porphobilinogen, III/ Coproporphy- (sometimes) Protoporphyrinogen rin I ratio >2 Mito- ALA chon- Coproporphyrin III, Coproporphyrin, dria Protoporphyrin Protoporphyrinogen Protoporphyrinogen Variegate por- AD Yes Yes IX > Copropor- Protoporphyrin NA oxidase oxidase gene phyria (VP) Porphobilinogen, Protoporphyrin IX phyrin III (sometimes) ALA 2+ Erythropoietic Fe Ferrochelatase Ferrochelatase gene protoporphyria AR No Yes NA Protoporphyrin Protoporphyrin Protoporphyrin Heme (EPP) The23 Southwest Respiratory and Critical Care Chronicles 2016;4(15) Doungporn Ruthirago,et al Acute porphyrias and porphyric
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