Abstract
Porphyria is a rare inherited metabolic disorder that results from mutations in the genes coding for the enzymes involved in heme biosynthesis. Deficiency of these enzymes leads to a backup build of porphyrins in the tissues, leading to neurovisceral and/or cutaneous manifestations. Acute porphyrias, which are of most interest to anesthesiologists, are precipitated by the induction of δ-aminolevulinic acid synthase by drugs, hormones, alcohol, and smoking. Common clinical manifestations of acute porphyria are neuropsychiatric abnormalities as well as sensorimotor and autonomic neuropathy. Diagnosis of acute porphyria requires high index of suspicion in any patient with unexplained acute abdominal pain and neuropathy. Management is based on avoiding the triggers of an acute crisis. Treatment of an acute attack mainly includes analgesics and symptomatic treatment. Heme and its derivatives may also be given in severe cases.
Keywords
porphyria, acute intermittent porphyria, hereditary coproporphyria, variegate porphyria
Case Synopsis
A 36-year-old woman with a history of intermittent abdominal pain was scheduled for elective laparoscopic cholecystectomy. Anesthesia and surgery were uneventful. On the first postoperative day, the patient was noted to be restless and was complaining of severe abdominal pain and vomiting. Her vital signs were heart rate 124 beats per minute, blood pressure 184/102 mm Hg, temperature 37.5° C, and respiratory rate 20 breaths per minute. The nurse informs the on-call resident that the patient’s urine is dark. During the resident’s assessment, the patient starts to shake in an attack of generalized seizure after which she is transferred to the surgical intensive care unit for further assessment and management.
Problem Analysis
Definition
Porphyria is a rare inherited metabolic disorder that results from mutation in any of the genes coding for the eight enzymes involved in heme biosynthesis. Partial deficiency in any of these enzymes can lead to accumulation of porphyrins and their precursors in the tissues, leading to neurovisceral and/or cutaneous manifestations.
Patients with porphyria can be misdiagnosed, and latent carriers of the disease may remain asymptomatic. The disease is transmitted most often by an autosomal dominant path. Everyone inherits two copies of the heme synthetic enzyme genes. Mutation of one allele, which results in a 50% reduction in enzyme activity, may be completely asymptomatic until the stresses on the heme synthetic system (as noted in the case synopsis) provoke an acute problem.
Recognition
The first and rate-limiting step in heme biosynthesis pathway is the conversion of glycine and succinyl coenzyme A to δ-aminolevulinic acid (ALA) by δ-aminolevulinic acid synthase (ALAS), which is negatively regulated by heme ( Fig. 19.1 ). Acute porphyrias are precipitated by the induction of ALAS to increase heme synthesis, but because of the enzyme defects, porphyrins and their precursors build up in the tissues. Although the exact underlying mechanism for neuropathy is still unclear, the suggested two mechanisms are accumulated porphyrins causing neurotoxicity or the disturbed heme metabolism affecting neuronal function.
Classification of Porphyria
Several classifications have been proposed for porphyria:
- 1.
Depending on the organs in which porphyrins and their precursors accumulate, they are classified into hepatic and erythropoietic (bone marrow).
- 2.
Depending on their clinical presentation, they are classified as follows:
- a.
Acute porphyrias: ALA dehydratase (ALAD) porphyria, acute intermittent porphyria (AIP), hereditary coproporphyria (HC), and variegate porphyria (VP) (see Fig. 19.1 ).
- b.
Nonacute porphyrias: congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EP).
- a.
Of the acute porphyrias, ALAD porphyria and AIP predominantly present with neurovisceral manifestations. The nonacute porphyrias predominantly present with cutaneous manifestations (e.g., photosensitivity, skin fragility, and bullae). HC and VP can present with acute neurovisceral as well as cutaneous manifestations. Among all types, acute porphyrias are considered of most interest to anesthesiologists.
Clinical Presentation
Clinical manifestations of acute porphyria start with behavioral changes and psychiatric abnormalities that proceed to sensorimotor and autonomic neuropathy:
- •
Restlessness, anxiety, insomnia, depression
- •
Pain: severe poorly localized abdominal pain, pain in the back and the extremities
- •
Autonomic neuropathy: sweating, tachycardia, arrhythmias, hypertension, urinary retention, nausea, vomiting, and constipation (less commonly diarrhea)
- •
Motor neuropathy: proximal muscle weakness rather than distal weakness, bulbar and respiratory paralysis
- •
Sensory loss: numbness and paresthesia
- •
Confusion, hallucinations, convulsions from hyponatremia due to either syndrome of inappropriate antidiuretic hormone or repeated vomiting
- •
Dark reddish urine
- •
Death: common causes are cardiac arrest and pneumonia from prolonged mechanical ventilation
Diagnosis of acute porphyria requires a high index of suspicion in any patient with unexplained acute abdominal pain, confusion, and neuropathy. Acute attacks can be fatal if misdiagnosed and left untreated. Once acute porphyria is suspected, urine should be checked for detection of elevated levels of porphobilinogen (PBG) and/or ALA. PBG levels can be as high as 10 times the upper normal level. Measurement of ALA is not essential for the diagnosis but can be helpful for differentiation of AIP from ALAD porphyria. Fecal levels of porphyrins can help differentiate HC and VP from other types of acute porphyria. In addition, erythrocytes may also show reduced activity of PBG deaminase enzyme; however, 5% of porphyria patients may not express enzyme defect in their red blood cells. DNA tests can also detect the specific gene mutations and determine the type of porphyria. Enzyme activity assays and DNA testing are not necessary for the diagnosis of an acute attack, but are helpful in the diagnosis of uncertain cases and in screening of family members of newly discovered cases.
Several investigations can be done to aid in the diagnosis of associated complications (e.g., electrocardiogram for detection of arrhythmias, magnetic resonance imaging of the brain showing reversible white matter densities resembling posterior reversible encephalopathy in blind patients).
Risk Assessment
There are fewer than 200,000 cases of porphyria in the United States. Worldwide prevalence of porphyria is around 0.5 to 10 per 100,000 with predominance in females around their third to fourth decades of life. However, ALAD porphyria is extremely rare with very few reported cases. In AIP, over 400 gene mutations for PGB deaminase have been identified, yet only 10% to 20% of the carriers develop clinical manifestations.
Different risk factors that can precipitate an acute attack have been identified. Induction of heme-containing hepatic enzyme cytochrome P-450 by drugs (e.g., barbiturates, griseofulvin, and sulfonamides), hormones (estrogen, progesterone), smoking, and alcohol use stresses the defective heme synthesis pathway, leading to accumulation of porphyrins. In addition, fasting and fever may induce heme oxygenase (enzyme that degrades heme to biliverdin), leading to depletion of the heme stores, which in turn increases ALAS activity. Psychological stress is another risk factor that can trigger an acute crisis ( Box 19.1 ).
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