An update of clinical management of acute intermittent porphyria

Figures & data

Figure 1 Precipitating factors and pathogenesis of an acute attack in AIP.

Notes: Several exogenic and endogenic factors induce heme biosynthesis via direct or indirect activation of ALA synthase. In AIP patients with inherited deficiency of HMBS, this results in accumulation of neurotoxic porphyrin precursors (ALA and PBG) in tissues and circulation. Heme, the end product of heme biosynthetic pathway, regulates transcription of ALA synthase via negative feedback and can be used in the treatment of an acute attack.
Abbreviation: AIP, acute intermittent porphyria.

Table 1 The laboratory investigations to confirm AIP and other acute porphyrias

Abbreviations: AIP, acute intermittent porphyria; U-PBG, porphobilinogen in urine; U-ALA, δ-aminolevulinic acid in urine; B-, whole-blood metabolites; P-, metabolites in plasma; U-, metabolites in urine; F-, metabolites in feces; HCP, hereditary coproporphyria; VP, variegate porphyria; HMBS, hydroxymethylbilane synthase; Erc-HMBS, HMBS activity in erythrocytes; PPOX, protoporphyrinogen oxidase; Ly-PPOX, PPOX activity in lymphocytes; CoproOX, coproporphyrinogen oxidase; erc-CoproOX, CoproOX activity in erythrocytes.

Figure 2 Staging of an acute attack in connection with precipitating factors and recommendations of heme therapy.

Note: Treatment with heme preparations: recommended (thin solid arrow), usually unnecessary (dotted arrow), influence of precipitating factors and connection with staging of acute attack (thick gray arrow).
Abbreviations: CNS, central nervous system; d, days.

Table 2 The key symptoms indicating acute porphyria

Intensive acute or recurrent abdominal pain without peritoneal signs or other obvious causes, especially if associated with

• Dysautonomia (tachycardia, hypertension, nausea, vomiting, constipation)

• Dark urine (due to porphyrins)

• Any neurological or psychiatric manifestation

• Hyponatremia

Hypertensive crisis

• Associated with abdominal pain

Acute or recurrent motor/sensorimotor polyneuropathies, especially if associated with

• Abdominal pain or dysautonomia, commonly preceding neuropathy

• Signs of central nervous system involvement

• Hepatopathy or hyponatremia

• Mainly axonopathy on nerve conduction studies

• Normal cerebrospinal fluid

Acute encephalopathy with no obvious etiology, especially if associated with

• Dysautonomia or pain

• Posterior reversible encephalopathy syndrome (PRES) on brain magnetic resonance imaging (MRI) or normal MRI

• Normal cerebrospinal fluid

Epileptic seizures or acute psychosis as a sign of acute encephalopathy with no obvious etiology, especially if associated with

• Hyponatremia

• Drug resistant

• Premenstrual

Rhabdomyolysis with no obvious etiology, especially if associated with

• Abdominal pain

• Hyponatremia

Table 3 Clinical manifestations and treatment of an acute attack

Signs and symptoms	Medications
I. Specific therapy	Heme preparations (3–4 mg/kg/d for 3–4 consequent days) if opiates are insufficient, or an acute attack is proceeding
II. High carbohydrate loading and supportive treatment	Glucose and other fluid infusions and follow-up of electrolytes, carbohydrate rich food
III. Symptomatic therapy
Autonomic neuropathy
Abdominal and/or back pain	Opiates iv/im bolus or in severe cases as infusion
Tachycardia, arrhythmia	Beta blockers, telemetry
Hypertension	Beta blockers, clonidine
Constipation	Lactulose
Vomiting	Phenothiazine,a olanzapine, lorazepam
Urinary retention	Urethral catheter
Peripheral neuropathy
Respiratory muscle paresis	Mechanical ventilation
Pneumonia	Antibioticsa except sulfonamides
Muscle weakness	Rehabilitation
Cranial neuropathy	Nasogastric tube for the bulbar paresis
Pain in extremities, back pain	Opiates, paracetamol, anti-inflammatory drugs
Numbness in extremities
Encephalopathy
Mental changes
Insomnia and/or anxiety	Most benzodiazepinesa including zopiclone
Hallucinations	Phenothiazines,a olanzapine
Convulsions	Correction of hyponatremia and hypertension, diazepam Gabapentin, levetiracetam if prolonged treatment is needed
Metabolic changes
Hyponatremia (SIADH)	P-Na >125 mmol/L: water restriction due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) P-Na ≤125 mmol/L or patients with seizures or unconscious: infusion of saline. Correction ≤12 mmol/L/day. Be aware of pontine myelinolysis
Acute renal failure	Fluid therapy, hemodialysis
Rhabdomyolysis	Fluid therapy
Hepatopathy	Follow-up of alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
Dark urine	Follow-up of U-PBG and U-ALA

Note:

a Most of the medications in the group are well tolerated.

Abbreviations: iv/im, intravenous/intramuscular; U-PBG, porphobilinogen in urine; U-ALA, δ-aminolevulinic acid in urine.

Table 4 Signs, symptoms, and metabolites followed during an acute attack

To be followed	Severe complication
Signs and symptoms
Pain, VAS
Blood pressure	Hypertensive crisis
Heart rate, telemetry	Palpitation, arrhythmia (atrial or ventricular)
Defecation	Constipation, paralytic ileus
Urination	Urinary retention, bladder paresis, oliguria
Respiratory rate	Respiratory insufficiency, pneumonia
Oximetry	Hypoxemia
Neurological status	Tetraparesis, bulbar palsy, seizures, unconsciousness, hallucinations
Electrolyte imbalance	Hyponatremia, SIADH, renal failure
Metabolites
K, Na, Mg, Ca	Hyponatremia, hypokalemia/hyperkalemia, hypomagnesemia
Glucose	Hypoglycemia/hyperglycemia
Creatinine	Acute renal failure, interstitial nephritis
CK	Rhabdomyolysis
ALT	Mild hepatopathy

Abbreviations: VAS, visual analog scale, from 0 to 10 cm; CK, creatinine kinase; ALT, alanine aminotransferase; SIADH, syndrome of inappropriate antidiuretic hormone secretion.