Abstract
Patients with acute/inducible porphyrias are at risk of porphyric crisis, particularly in the perioperative period. Drugs administered in the perioperative period, the condition requiring the surgery, stress, and/or fasting may precipitate acute attacks of porphyria. Porphyric crises presenting with abdominal pain, motor weakness, and other neurologic symptoms may be fatal if unrecognized and untreated. We present a typical case and review the perioperative management of such patients in the context of the disease pathophysiology.
Keywords
porphyria, genetic disorder, heme, perioperative planning, drug reactions
Case Synopsis
An anxious 24-year-old woman presents with nausea, vomiting, and abdominal pain and is scheduled for exploratory laparotomy. Past history is remarkable for a negative exploratory laparotomy 2 years ago. Blood pressure is 150/90 mm Hg, and pulse is 105 beats per minute; the physical examination reveals abdominal tenderness. Electrolyte levels and white blood cell count are normal. With direct questioning about family history, the patient declares that her mother may have had porphyria.
Problem Analysis
Definition
A good understanding of the basic deficiency and interaction with anesthesia and the stresses of surgery can prevent an acute attack in susceptible patients with inducible porphyria.
Porphyrias are a heterogeneous group of genetic disorders where a deficiency in an enzyme combined with environmental stresses can produce an acute attack and accumulation of intermediary products of heme synthesis that can cause mild to life-threatening symptoms. Although porphyrias can be classified on the basis of the underlying genetic defect ( Fig. 86.1 ), the simple clinical division into inducible/acute and noninducible/chronic forms remains useful. An example of the latter is porphyria cutanea tarda (PCT), the most frequent form of porphyria. Apart from the friability of the patient’s skin and the association with hepatitis C, human immunodeficiency virus, or alcohol abuse, PCT presents no anesthetic concerns and does not restrict the choice of drugs. In contrast, all patients with acute/inducible porphyrias are at risk of porphyric crisis, particularly in the perioperative period. Drugs administered in the perioperative period, the condition requiring surgery, stress, and/or fasting may precipitate acute attacks of porphyria. If the attack goes untreated or unrecognized, it can be fatal. Conversely, control of precipitating factors and/or prompt treatment averts or mitigates the attack and allows the safe conduct of surgery. Therefore acute porphyrias present important anesthetic concerns.
Porphyrin synthesis occurs in all cells and is of particular importance in bone marrow and the liver. Porphyrins are essential components of proteins involved in the utilization, transport, and storage of oxygen. These proteins include the ubiquitous cytochrome oxidases of the respiratory chain, the hepatic cytochrome P450 enzymes, and oxygen storage and transport proteins such as hemoglobin. Synthesis of porphyrins involves a series of enzymes (see Fig. 86.1 ). Genes for key enzymes of porphyrin synthesis are duplicated in the genome, allowing for the separate regulation of heme synthesis in the liver and bone marrow. In the liver, most heme is used for the production of cytochrome P450 enzymes. Therefore regulation of heme synthesis and P450 production are regulated in a coordinated fashion.
The four acute porphyrias are acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and δ-aminolevulinic acid dehydratase–deficient porphyria (ADP). The gene defects that underlie the acute porphyrias are loss-of-function mutations and typically reduce enzyme activity by half. This reduction results from a pattern of inheritance that is recessive for the rare ADP or dominant with variable penetrance for the three more frequent acute porphyrias ( Table 86.1 ). Although the location of the defective hepatic enzyme in the synthetic pathway for heme varies among the acute porphyrias (see Fig. 86.1 ), all four may present with acute attacks that are similar in symptoms and treatment. It is unclear why enzymatic defects in chronic or erythropoietic porphyrias do not lead to acute attacks. HCP and VP may cause accumulation of excess porphyrins in the skin, where excitation by ultraviolet light causes blistering and scarring skin lesions.
| Porphyria | Incidence | Inheritance | Neurovisceral Symptoms | Photosensitivity |
|---|---|---|---|---|
| δ-Aminolevulinic acid dehydratase–deficient porphyria (ADP) | Exceedingly rare | Autosomal recessive | ++ | − |
| Acute intermittent porphyria (AIP) | 1:10,000 Higher in Scandinavia | Autosomal dominant | +++ | − |
| Hereditary coproporphyria (HCP) | Rare 1:1,000,000 | Autosomal dominant | ++ | + |
| Variegate porphyria (VP) | 1:300,000 Higher in South Africa | Autosomal dominant | ++ | + |
Recognition
Because symptoms can be nonspecific and varied, acute attacks of inducible porphyrias are difficult to recognize in the perioperative period. Typical symptoms and frequency of occurrence are summarized in Table 86.2 . Attacks rarely occur before puberty and seldom recur throughout adult life. They last for several days and are characterized by intense, steady, and poorly localized abdominal pain. The intensity of the pain contrasts sharply with the paucity of physical findings, sometimes resulting in emergent exploratory laparotomies. Nausea, vomiting, and decreased bowel sounds are common but do not dominate the clinical picture, whereas fever, leukocytosis, and/or abdominal tenderness is usually absent. Acute attacks of inducible porphyrias may involve the peripheral nervous system in the form of a proximally accentuated motor weakness. This weakness occasionally occurs after resolution of the abdominal pain and may resemble Guillain-Barré syndrome without the characteristic albumin increase in cerebrospinal fluid. Cranial nerves and sensory nerves may be affected, and progression of neurologic involvement to respiratory and bulbar paralysis and death is possible. In one-quarter of patients, the central nervous system can also be involved in the form of psychiatric symptoms such as anxiety, hallucinations, and/or paranoia. Generalized seizures may occur as a neurologic manifestation of central nervous system involvement or as a manifestation of severe hyponatremia caused by inappropriate secretion of antidiuretic hormone and/or vomiting. If suspected, the diagnosis of acute porphyria can be confirmed by screening for and quantifying the porphyrin precursors δ-aminolevulinic acid and porphobilinogen in the urine. Daylight can convert the colorless porphobilinogen to porphyrins that cause a darkening and red-to-purple discoloration of the urine. Resolution of symptoms is usually rapid, but weakness may persist for days or months.
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