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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 . Acute porphyrias are specific types of porphyrias characterized by the presence of acute attacks that usually present with , 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 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; ; 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 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) 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 (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 or . 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 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 and sulfa , induce Pathophysiology 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. and explains why acute porphyria is pre- 9 Heme is synthesized in the and and cipitated by starvation. is required for the synthesis of hemoproteins-hemo- globin, , and , 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 , abdominal distension, is inhibited by heme in a negative feedback pathway. followed by pain, , , and . 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 where two ALAs are converted viduals when environmental triggers activate ALAS1, to (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 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 porphyrias and porphyric neuropathy - - NA NA NA phyrin phyrin IX Free and Zn (sometimes) Zn protopor Erythrocyte Uroporphyrin ± Zn protopor protoporphyrin Protoporphyrin Uroporphyrin I, Coproporphyrin I NA Plasma porphyrin porphyrin (sometimes) (sometimes) (sometimes) Uroporphyrin Uroporphyrin, Uroporphyrin, Uroporphyrin, Heptacarboxyl Heptacarboxyl Protoporphyrin Protoporphyrin Protoporphyrin Coproporphyrin Coproporphyrin Coproporphyrin, ------NA Feces rin III, phyrin III (sometimes) yl porphyrin rin I ratio >2 Uroporphyrin rin, Heptacar Coproporphy Protoporphyrin Protoporphyrin Protoporphyrin IX > Copropor Coproporphyrin Isocoproporphy Isocoproporphy boxyl porphyrin, Coproporphyrin I Coproporphyrin I rin, Heptacarbox III/ Coproporphy Laboratory findings (increased level) Laboratory findings (increased NA NA ALA ALA ALA, ALA, Urine porphyrin porphyrin Uroporphyrin Uroporphyrin, Heptacarboxyl Heptacarboxyl Uroporphyrin I, Porphobilinogen, Porphobilinogen, Porphobilinogen, Uroporphyrin III, Coproporphyrin I Coproporphyrin III Coproporphyrin III, Coproporphyrin III, No No Yes Yes Yes Yes Yes Yes Yes Cutaneous involvement No No No No No Yes Yes Yes Yes Neuro- Clinical presentation visceral involvement AR AR AR AR AD AD AD AD Mode of X-linked dominant inheritance - - - - (AIP) (EPP) (CEP) (HEP) (XLP) (HCP) (fPCT) Diseases porphyria porphyria phyria (VP) cutanea tarda phyria (ADP) Variegate por Variegate Erythropoietic protoporphyria protoporphyria deficiency por Hepatoerythro- poietic porphyria ALA ALA dehydratase Congenital eryth Hereditary copro Acute intermittent Familial porphyria X-linked dominant ropoietic porphyria oxidase gene oxidase gene deaminase gene Porphobilinogen ALA dehydratase ALA (gain of function) Uroporphyrinogen Uroporphyrinogen Uroporphyrinogen III cosynthase gene ALA synthase gene ALA decarboxylase gene decarboxylase gene Ferrochelatase gene Protoporphyrinogen Coproporphyrinogen oxidase oxidase deaminase III cosynthase ALA synthase ALA decarboxylase decarboxylase Ferrochelatase Porphobilinogen ALA dehydratase ALA Uroporphyrinogen Uroporphyrinogen Uroporphyrinogen Enzymatic defects (increased enzyme) Protoporphyrinogen Coproporphyrinogen

2+ Heme Fe

Porphobilinogen

Protoporphyrin IX Protoporphyrin

Coproporphyrinogen Uroporphyrinogen III Uroporphyrinogen

Hydroxymethylbilane Protoporphyrinogen Glycine + Succinyl CoA + Succinyl Glycine Delta-Aminolevulinic acid Delta-Aminolevulinic

I Uroporphyrinogen Coproporphyrinogen - - - - -

Mito chon dria Mito chon dria Cyto plasm Table

The Southwest Respiratory and Critical Care Chronicles 2016;4(15) 23 Doungporn Ruthirago,et al Acute porphyrias and porphyric neuropathy

rotoxicity of accumulated porphyrin precursors, es- Classifications pecially ALA. Aminolevulinic acid increases in acute attacks of porphyria and other porphyria-like neurop- The porphyrias may be classified based on athies, such as and hereditary tyrosin- the primary clinical manifestations as either acute or emia.11 Aminolevulinic acid induces the formation of cutaneous or by the major site of the enzymatic de- free radicals, causing oxidative damage to cell struc- fect as either hepatic or erythropoietic.1 This review tures.12 The second mechanism is energy deficits due will be based on porphyria classification by clinical to inadequate heme synthesis, which is an essential manifestation and will mention nine types of porphyria component of electron transport system. Dysfunc- according to the enzyme deficiency in each step of tion of Na+/K+ ATPase, which is energy-dependent, heme synthetic pathway with the exception of the X- causes abnormal axon transport and neural dysfunc- linked dominant protoporphyria which occurs from a tion.13 Energy deficits also cause impaired detoxifica- gain of function .3 Only four types of acute tion systems in which cytochrome P450 fails to detox- porphyrias are discussed in this review, and the five ify drugs and mitochondria cannot prevent oxidative types of cutaneous porphyrias are listed at the end of damage (Figure).14 the section. The Table shows the classification of por- phyrias, related enzymatic deficiencies, gene muta- tions, mode of inheritance, clinical presentations, and laboratory finding.

Figure-Schematic overview of the pathophysiology of porphyric neuropathy

Neuropathy occurs in 20-68% of porphyria pa- Acute porphyrias tients.2 The typical pattern of porphyric neuropathy is predominantly motor axonal neuropathy.15,16 Abdomi- An acute life-threatening crisis or acute at- nal pain usually starts days to weeks before neuropa- tacks are characteristic of acute porphyrias. Patients thy. The motor neuropathy is normally symmetrical may present with prodromal symptoms, such as be- and begins in proximal part of the upper extremities. havioral change, insomnia, anxiety, and later develop However, the patterns of motor involvement are vari- symptoms of acute attack. Acute attacks usually last able.10 Sensory neuropathy is less common, presents no longer than 1-2 weeks before entering a recovery as neuropathic pain and distal limb paresthesia, and phase; they can be fatal if the patient develops severe sometimes occurs in proximal distribution.2,17 Cranial neurological dysfunction. The acute attacks usually nerve involvement can also occur but is infrequent. occur after puberty and rarely occur after menopause. Less than 10% of patients develop recurrent acute at- tacks.3 The mode of inheritance of acute porphyrias

24 The Southwest Respiratory and Critical Care Chronicles 2016;4(15) Doungporn Ruthirago,et al Acute porphyrias and porphyric neuropathy

is autosomal dominant with incomplete penetrance nonspecific as it can be found in liver diseases. Ge- except for aminolevulinic acid dehydratase deficiency netic testing for the CPOX mutation should be per- porphyria which is an autosomal recessive disorder. formed to confirm the diagnosis of HCP in both symp- tomatic patients and asymptomatic family members.1 1. Acute Intermittent Porphyria (AIP) 3. (VP) Acute intermittent porphyria is the most com- mon acute porphyria with an incidence of 1 in 20,000.1 Variegate porphyria, similar to HCP, presents It occurs due to a mutation in the porphobilinogen with neurovisceral symptoms similar to other acute deaminase (PBGD) gene, which causes decreased porphyrias though frequently less severe. Patients PBGD enzyme activity (previously called hydroxy- may present with cutaneous photosensitivity develop- methylbilane synthase). Despite being inherited in an ing blistering skin lesions more frequently than HCP autosomal dominant pattern, AIP has variable pene- patients. The incidence of VP is highest in South trance which explains why some patients do not have Africa. It occurs from a mutation of the protoporphy- a family history and why more than 90% of patients rinogen oxidase (PPOX) gene, causing decreased with an abnormal gene never develop an acute at- PPOX enzyme activity. Urine delta-ALA and PBG are tack. Acute attacks occur in patients with genetic sus- elevated during acute attacks but usually are normal ceptibility who also have precipitating factors, such between attacks. Plasma porphyrins are increased as hormones, drugs, or starvation.3 during attacks. In asymptomatic carriers, urine tests show elevated coproporphyrin, and fecal tests show Acute attacks of AIP usually develop over excess coproporphyrin and protoporphyrin. Genetic two or more days with symptoms of abdominal pain, testing should be performed to confirm the diagnosis.1 muscle weakness, neuropathy, sympathetic overac- 1 tivity, , but no skin lesions. Urine tests 4. Aminolevulinic acid dehydratase deficiency porphy- during acute attacks demonstrate elevated urine por- ria (ADP) phobilinogen (PBG) which is sensitive and specific for acute porphyrias. Low PBGD enzyme activity in red Aminolevulinic acid dehydratase deficiency cells confirms the diagnosis of AIP; however, porphyria is the only acute porphyria that is transmit- some patients may not have an enzyme deficiency. ted in an autosomal recessive pattern. It is extremely The gold standard for diagnosis of AIP is genetic test- rare with less than 10 cases reported worldwide. It ing for specific .1, 3 occurs from a mutation of the aminolevulinic acid de- hydratase (ALAD) gene, causing decreased ALAD 2. Hereditary Coproporphyria (HCP) enzyme activity. Patients present with symptoms of acute attack similar to AIP. Skin lesions are not pres- Patients with HCP present with classic neu- ent. Laboratory tests during acute attacks show el- rovisceral symptoms of acute attack. In some cases evated urine ALA but normal PBG.1 cutaneous photosensitivity is also present associated with blistering skin lesions similar to those in porphyr- Cutaneous porphyrias ia cutanea tarda (PCT). Hereditary coproporphyria occurs from a mutation in the coproporphyrinogen 5. Sporadic and familial por- oxidase (CPOX) gene, causing decreased CPOX en- phyria cutanea tarda (sPCT and fPCT) zyme activity. Laboratory tests during acute attacks 6. Erythropoietic protoporphyria (EPP) show elevated urine delta-ALA and PBG. Fecal cop- 7. X-linked dominant protoporphyria (XLP) roporphyrin in appropriate ratio is sensitive for diag- 8. Congenital (CEP) nosis of HCP. In asymptomatic carriers, urine and fe- 9. Hepatoerythropoietic porphyria (HEP) ces have elevated coproporphyrins, especially type III. However, isolated excess urine coproporphyrin is The details of cutaneous porphyrias are beyond the

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scope of this review. However, the summary of their entation, , and paranoia. Chronic pain enzymatic defects, mutations, modes of inheritance, and depression may also be present in some patients clinical presentations, and laboratory findings are also after frequent exacerbations and are associated with shown in the Table. increased risk of suicide.

Clinical manifestations Cutaneous manifestations

The presentation of the acute porphyrias is va- Photosensitivity presenting as redness, pain, riable and nonspecific; patients usually develop symp- swelling in sun-exposed areas, and bullous lesions 1 toms in several systems. occurs in several types of porphyrias. Cutaneous le- sions were reported in 60% of patients with variegate Visceral manifestations porphyria and 5% of hereditary coproporphyria but are not found in acute intermittent porphyria.23 Abdominal pain is the most common and most troublesome presenting symptom of acute porphyria Other manifestations with an occurrence rate of 85-95%.18 Patients usually complain of constant, poorly localized pain associat- Hyponatremia occurs in 30% of patients, some- ed with nausea, vomiting, abdominal distension, and times due to the syndrome of inappropriate antidiuret- constipation that mimics an acute . ic hormone secretion but also due to excessive gas- and leukocytosis rarely occur since the pain is neuro- trointestinal loss from vomiting, poor oral intake, and 18 pathic and not inflammatory. Bladder dysfunction can excess renal losses. Dark or red urine may also be also develop with urinary retention, incontinence, and an early symptom, but it does not always occur during dysuria.19 acute attacks. If present, it suggests the diagnosis. Patients with porphyrias also have an increased in- Neurological manifestations cidence of and chronic kidney disease and have an increased risk for chronic 17 Central nervous system symptoms, such as and . and encephalopathy, are reported in 5-30% and 2-10% of patients, respectively. Seizure in acute Diagnosis porphyrias may be triggered by hyponatremia and hy- pomagnesemia.10,20 In acute attacks associated with Porphyrias usually present with nonspecific encephalopathy, abnormal magnetic resonance im- symptoms. Therefore, laboratory tests are essential aging similar to that found in posterior reversible en- to confirm or exclude the diagnosis. Common investi- cephalopathy syndrome (PRES) has been reported.21 gations in acute porphyrias include biochemical tests can present as weakness, to measure porphyrins and porphyrin precursors, to sensory disturbances, pain, and respiratory muscle detect enzyme activities, and to confirm the diagnosis weakness in 20-68%, 7-38%, 20-70%, and 9-20%, with DNA tests. For patients who present with neurop- respectively.2, 10 Motor symptoms are more common athy, electrophysiological tests assist in differentiating than sensory symptoms. Autonomic dysfunction also the type of neuropathy. Pathological studies are not occurs commonly, presenting as , hyper- usually required for diagnosis but help improve the tension, restlessness, tremor, and sweating. understanding of porphyric neuropathy.

Psychiatric manifestations Biochemical tests

Psychiatric symptoms are reported in 20- Deficiency of enzymes in each type of porphy- 30% of patients during acute attacks.22 These include rias causes accumulation of different precursors and anxiety, depression, insomnia, restlessness, disori- intermediates. During acute attacks, these excess

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substances accumulate in the liver or bone marrow to screen for porphyria.1 If total plasma porphyrin is and later enter the blood. The water-soluble interme- increased, further tests should be done to confirm the diates are excreted in the urine, while the water-insol- diagnosis. uble intermediates are excreted in the feces.1 Porphy- rins are named according to the number of carboxyl Measurement of enzyme activity in erythro- groups as octacarboxyl porphyrin (uroporphyrin), hep- cytes (PBGD, ALAD) and lymphocytes (CPOX and tacarboxyl porphyrin, hexacarboxyl porphyrin, penta- PPOX) can help to support diagnosis of AIP, ADP, carboxyl porphyrin, tetracarboxyl porphyrin (copro- HCP, and VP, respectively.3 However, there is some porphyrin), tricarboxyl prophyrin (harderoporphyrin), overlap between the normal range and the spectrum dicarboxyl porphyrin (protoporphyrin). The more car- of porphyrias, and some mutations do not cause de- boxyl groups present, the more water-soluble is the ficiency in blood cells. It is recommended that an en- compound. Tricarboxyl and dicarboxyl prophyrins are zyme activity assay be used to detect carriers in the excreted in bile and feces, while coproporphyrin are family when a deficiency in the index case is already excreted in urine and feces.24 Porphyrin precursors, confirmed.1 such as ALA and PBG, are elevated in all types of acute porphyrias, except for ADP which has isolated Genetic tests ALA elevation. The gold standard test to confirm diagnosis of During acute attacks, the first-line tests with porphyria is DNA testing to identify specific mutations. high sensitivity and specificity are measuring urinary It can also be used to detect carriers of gene mutation ALA, PBG, and total porphyrins. If all the levels are in families after the mutation is identified in the index normal, acute porphyrias can be excluded. If the lev- case. DNA testing can detect more than 97% of dis- els are increased more than 5 times normal, acute ease-causing mutations, especially with significantly porphyria is highly possible, and second-line tests elevated PBG levels.1 Therefore, porphyrin precur- should be done to differentiate the type of porphyria. sors, such as ALA and PBG, and biochemical testing Nonspecific elevation of less than three times can be in plasma, urine, and feces should be done before found in dehydration.1 However, if the urine level is requesting a DNA test. DNA tests from blood samples done after the onset of acute attack, ALA and PBG can be done either during acute attacks or in asymp- levels can be normal. Urine porphyrins may remain tomatic phases. In patients who present with acute elevated longer than the precursors, but they are less attacks without skin lesions, the “Triple test” can be specific for porphyrias. Measurement of individual requested to detect mutations for AIP, VP, and HCP.1, porphyrins in plasma, urine, and feces can be done to 25, 26 help differentiate the type of porphyrias by using high 1, 24 performance liquid chromatography (HPLC). How- Electrophysiological findings ever, the patterns of elevation are difficult to interpret and other conditions can cause elevation of porphy- As porphyric neuropathy is fundamentally an rins. For example, liver diseases, some bone marrow axonal neuropathy with predominant motor nerve diseases and lead poisoning can cause increase in dysfunction, electrodiagnostic findings typically sup- total urine porphyrin and coproporphyrin. This pattern port this pattern of neuropathy. Nerve conduction is also found in hereditary coproporphyria and in var- studies (NCS) during acute attacks show reductions iegate porphyria.7 in compound motor unit action potential (CMAP) with relatively preserved conduction velocities. Conduction For cutaneous porphyrias and acute porphyr- abnormalities of sensory nerves are sometimes dem- ias with cutaneous manifestations, such as hereditary onstrated but are less common than motor nerves.27, coproporphyria and variegate porphyria, measure- 28 In later stages, when muscle weakness is more ment of plasma porphyrins when the patient presents prominent, NCS may show progressive reductions in with skin symptoms can be used as a first-line test CMAP amplitudes. Electromyography (EMG) demon-

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strates wide spread fibrillation potentials compatible Treatment with denervation, especially in proximal muscles. In later stages, EMG may show polyphasic motor unit Most patients who present with acute attacks action potentials with higher duration and amplitude, of porphyrias require hospitalization for pain control, predicting denervation and re-innervation patterns.29 hydration, and treatment of nausea and vomiting. Between acute attacks, even without clinical neu- Treatments can be broadly divided into symptomatic ropathy, NCS may show reduced inward rectification treatment, specific treatment of porphyrias, and coun- (IH), which indicates subclinical dysfunction of axonal seling. metabolism.15 During acute attacks, axon excitability recordings show depolarization of axonal membrane Symptomatic treatment secondary to impairment of Na+/K+ ATPase func- tion.10, 15, 30 Appropriate treatment in early phase of Abdominal and limb pain can be controlled porphyric attack can resolve these neuropathic pat- with acetaminophen, nonsteroidal anti-inflammatory terns. However, if the treatment is delayed or if the drugs, and as needed. Nausea and vomiting attack is severe, neuropathy may persist and only can be treated with promethazine, ondansetron, or partially improve over time.15 other antiemetic drugs. Maintaining water and elec- trolyte balance is very important. Adequate hydration The clinical manifestations of porphyric neu- is needed, as well as preventing hyponatremia which ropathy can overlap with Guillain-Barre syndrome can provoke . Constipation can be treated (GBS). The electrophysiological patterns of axonal with bulk laxatives or lactulose. Some patients who neuropathy, such as reduced amplitudes, relative have hypertension and tachycardia from sympathetic preservation of H reflexes, F waves and distal latency, overactivity may need β-blockers, such as proprano- minimal conduction slowing, and absence of conduc- lol and atenolol.3 Physical and speech therapy are tion block, may help differentiate it from demyelinating helpful for patients who develop muscle weakness or patterns typically found in GBS.2, 31 However, differen- bulbar involvement. Some patients with respiratory tiating porphyric neuropathy from the axonal type of muscle weakness may need mechanical ventilation. GBS is difficult and may need serial electrodiagnostic Close monitoring in the intensive care unit is needed studies and other laboratory tests. in patients with severe acute attacks. Insomnia and anxiety can be managed with . An- Pathological findings tipsychotic medications are sometimes required for psychotic symptoms.3, 4 Pathological studies demonstrate severe de- nervation of motor nerves and central chromatolysis Specific treatment of acute porphyrias of anterior horn cells, suggestive of dying-back Wal- lerian degeneration, with relatively spared sensory inhibits ALAS and decreases por- nerves. Muscle biopsy shows significant loss of nerve phyrin synthesis in the liver.34 Adequate carbohydrate fibers compatible with neurogenic change and limited and calorie intake is important to suppress disease changes of muscle denervation atrophy.27, 28, 32 activity and accelerate recovery. Intravenous glucose should be administered if the patients cannot toler- The proximal predominant pattern of porphyric ate oral diets. Intravenous heme (or ) 4 mg/kg/ neuropathy may be explained by retrograde axonal day, given daily for 4-14 days, is a specific and ef- transport of neurotoxic substances, such as ALA, from fective treatment if started early before severe nerve the distal part of the axon to motor neuron. Heme pre- damage occurs.35 It replaces heme deficiency in the cursors may enter at neuromuscular junctions which liver and suppresses production of porphyrin precur- do not have a blood-nerve barrier and are transport- sors. Some porphyria experts recommend starting ed initially to neurons innervating proximal muscles, hemin if symptoms do not improve within 1-2 days of causing proximal more than distal weakness.2, 33 intravenous glucose.1 It should be started in patients

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who have elevated urinary PBG levels. Delayed treat- psychiatric symptoms. Acute porphyrias occur from ment can lead to nerve damage, chronic pain, and environmental triggers in the presence of genetic sus- muscle weakness.10 Hemin has some side effects, ceptibility, leading to accumulation of porphyrins and such as phlebitis and coagulopathy, which could be their precursors. Porphyric neuropathy is believed to prevented by dilution with albumin and using develop from conditions that cause relative heme de- a central line or large peripheral vein. Less than 10% ficiency and neurotoxicity from porphyrin precursors. of patients with recurrent acute attacks need preven- The typical electrophysiological pattern of porphyric tive treatment with intravenous hemin and rarely liver neuropathy is axonal neuropathy with predominant transplantation.1, 3 motor involvement. The timely diagnosis and early initiation of specific treatment are important to prevent Counseling severe porphyric neuropathy and its sequelae. Symp- tomatic treatment during the attacks and counseling Counseling is one of the most important man- about carrier detection and avoidance of precipitating agement steps in acute porphyrias. Patients should factors should be provided to the patients. be advised to avoid precipitating factors. and porphyrinogenic drugs, such as barbiturates, sulfon- amide antibiotics, hormonal substances, some anti- epileptic medications, should be avoided. Infections Author Affiliation: Doungporn Ruthirago and Parunyou should be treated.1 The patients and their physicians Julayanont are residents in the Department of should check with reliable sources regarding the at Texas Tech University Health Sciences Center in safety of drugs before initiating any new treatment. Lubbock, TX. Supannee Rassameehiran is a resident in the Department of Internal Medicine at TTUHSC in Lubbock, TX. Adequate carbohydrate and calorie intake is impor- Received: 04/19/2016 tant. Porphyria patients should be educated to avoid Accepted: 06/14/2016 starvation. A dietitian should be consulted if weight Reviewers: Catherine Jones MD 1, 3 loss is truly necessary. Genetic counseling for the Published electronically: 07/15/2015 patient and their relatives is another important issue. Conflict of Interest Disclosures: None Children of patients with acute porphyrias have a 50% chance of acquiring an abnormal gene. for relatives to detect heterozygous carriers and educating them to avoid precipitating factors can prevent acute attacks. References

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