Variegate Porphyria Clinical Presentation

Updated: Dec 20, 2019
  • Author: Carol E Cheng, MD; Chief Editor: Dirk M Elston, MD  more...
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Presentation

History

A family history of variegate porphyria may or may not be present. Studies of the clinical penetrance of the variegate porphyria trait found that ~60% of all individuals harboring a single protoporphyrinogen oxidase mutation remained silent carriers. [25, 26] Among the 40% who did manifest symptoms, photosensitivity alone was the presenting complaint far more often than neurological disturbances alone, while only a small minority (4-8%) experienced both types of symptoms. Skin lesions were the presenting sign in approximately 80% of a group of 70 European patients identified. [20]

A porphyric attack is typically described as abdominal discomfort that may have progressed over several hours to severe pain extending into the back, chest, arms, and legs. Nausea with vomiting, constipation, hypertension, tachycardia, anxiety, and agitation may be reported. Pain and weakness developing in extremities indicates an accelerating attack that may progress to flaccid quadriparesis. Central nerve paralysis, respiratory distress, confusion and bizarre behavior, seizures, or coma may develop before the patient is assessed by medical personnel. Attack episodes of variegate porphyria can often be linked to history of a new medication. Factors historically associated with the onset of attacks in other acute porphyrias (eg, hormonal fluctuations due to menses, pregnancy or therapeutic hormones, infections, other stressors) appear to be less often responsible for attacks in variegate porphyria. [24]

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Physical Examination

Photocutaneous lesions, the predominant presenting signs of variegate porphyria, include mechanical fragility, blistering, milia, furrowing, and scarring in sun-exposed skin. Hypertrichosis, dyspigmentation, sclerodermoid changes, and a weather-beaten or leathery skin texture may be present. Children with biallelic variegate porphyria experience photosensitivity of mutilating severity. [23, 27]

Neurovisceral dysfunctions occur less frequently and recur far less often in variegate porphyria than in acute intermittent porphyria (AIP). [24] Pain in variegate porphyria may become excruciating; uncontrolled vomiting can lead to dehydration. Deteriorating neurological function produces multiple sequelae, including peripheral neuropathy. [28] Initial limb weakness may progress to areflexic quadriparesis. Respiratory failure may occur. Heart rate and blood pressure can rise to critical levels. During such crises, dark-orange or reddish urine is excreted; bowel and bladder function may be disturbed. Ten to twenty percent of patients with acute porphyria experience seizures, which are most often characterized as tonic-clonic or focal with impaired awareness. [28] Coma may ensue.

Confusion, disorientation, agitation, mania, depression, and schizophrenialike behavior have all been reported. Psychiatric symptoms were noted in 80% of 18 Finnish patients during attacks, with 25% described as delirious and psychotic. [6] In the larger South African experience, however, neuropsychiatric disturbances are infrequent in variegate porphyria, especially in the absence of other signs and symptoms of an attack. [3] Metabolic encephalopathy may occur during variegate porphyria crises, contributing to some of these phenomena, as well as to seizures and coma. There has been one case study that reported posterior reversible encephalopathy syndrome (PRES) as a complication of variegate porphyria. [29]

Hypervolemia and hyponatremia noted in more severe attacks may involve renal salt wasting, inappropriate antidiuretic hormone secretion, or infusion of inappropriate replacement fluids. Hypomagnesemia may also be present.

Because variegate porphyria may variably manifest with only neurovisceral symptoms, with only cutaneous photosensitivity, or with both, other diagnoses to be considered include porphyrias that share either type or both types of symptoms and nonporphyric bullous disorders that occur in sun-exposed skin. Acute ascending polyneuropathy (Landry-Guillian-Barre syndrome) may resemble aspects of porphyric neuropathies in causing progressive paralyses that may affect respiratory muscles, in altering sensation or producing pain, and in disordering autonomic nervous system functions.

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Complications

Complications can include renal disease [30] and hepatocellular carcinoma. [31, 32]

Chronically uncontrolled hypertension from acute porphyria can lead to renal impairment. [30]

Six cases of hepatocellular carcinoma (a known complication of acute intermittent porphyria in patients as young as 37 years) discovered at ages ranging from 54-81 years in patients with variegate porphyria were reviewed. [31] One had no symptoms of porphyria prior to diagnosis of the cancer. Annual screening for hepatocellular carcinoma in patients with any acute porphyria, and of asymptomatic carriers of mutations for any acute porphyria, by hepatic ultrasound and serum α-fetoprotein studies beginning at age 47 years is the practice of one porphyria specialist center. [31] Additional variegate porphyria-hepatocellular carcinoma cases included one presenting at age 48 years. [32] Liver imaging at 6-month intervals in patients with any acute porphyria aged 50 years or older with long-standing, unremitting elevations in porphobilinogen or porphyrins is another expert recommendation. [33] As of 2015, there have been 9 reported cases of hepatocellular carcinoma in patients with variegate porphyria, although the link between the two remains tenuous. [32, 34]

Gallstones, reported in a small number of patients, may be the presenting sign. [35] High levels of protoporphyrin in bile may lead to gallstone formation. Surgical cholelithectomies or cholecystectomies must be performed with care to avoid anesthetics that can induce attacks.

Patients with acute porphyrias may be subject to attacks during pregnancy, [36, 37] but these are infrequent and most often brought on by inadvertent use of unsafe medications. [37, 38] When acute symptoms occur during pregnancy, management recommendations follow the same outlines as for nonpregnant women, including the use of an intravenous heme analogue if necessary. [38] Several pregnant women manifesting acute porphyric attack symptoms have been treated with intravenous hemin (as the heme analogue heme arginate) without adverse fetal effects. [39]

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