Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias Workup

Updated: Jun 28, 2018
  • Author: Norman C Reynolds, Jr, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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Laboratory Studies

In acute disease, blood or urine tests are definitive. Although DNA tests are being developed using polymerase chain reactions, the current state-of-the-art testing relies on the identification of abnormally high levels of key substrates. In the diseases of tetrapyrrole metabolism, the value of DNA analysis will not be first-order identification but rather the clarification of new mutations or assistance in differentiating between types of hepatic porphyria, which have only borderline elevations of metabolites or inconclusive differences in metabolite results. [10, 11]  Lab findings include the following:

  • Refsum disease - Increased phytanic acid in serum

  • Porphyrias - Increased ALA and porphobilinogen (PBG) in the urine and serum (A work-up algorithm is available online from the American Porphyria Foundation.)

  • In quiescent or latent periods, monitoring of characteristic metabolites in serum is recommended. Refsum disease: Monitor phytanic acid to check the adequacy of dietary restrictions. Porphyrias: Monitor erythrocyte enzymes and quantitative porphyrins in 24-hour collections of urine and stool.

  • Erythrocyte enzymes: Low values are confirmatory and in some cases diagnostic.

  • Acute intermittent porphyria: Watch for low levels of porphobilinogen deaminase and uroporphyrinogen decarboxylase (also low in porphyria cutanea tarda). [12]

  • Porphyria cutanea tarda: Uroporphyrinogen decarboxylase [1] level is low, but porphobilinogen deaminase level is normal.

  • Variegate porphyria and other porphyrias: levels of both enzymes are normal. Make this diagnosis only from quantitative porphyrins.

  • Quantitative porphyrins are measured from 24-hour collections of urine and stool.

  • Acute intermittent porphyria: Urinary ALA and PBG levels are increased. Stool porphyrin levels are either normal or only marginally elevated.

  • Variegate porphyria: Urinary ALA and PBG levels are increased. Fecal protoporphyrin and, to a lesser extent, coproporphyrin levels are excessive.

  • Hereditary coproporphyria: Excessive excretion of urinary and fecal coproporphyrins is noted. [13]

  • Protoporphyria: As distinguished from variegate porphyria, abnormal excretion levels typically are limited to the stool. Levels of protoporphyrins are very high and, occasionally, coproporphyrin levels are elevated somewhat.

  • Porphyria cutanea tarda: Elevation of urinary uroporphyrin levels is characteristic. While ALA and PBG usually are not present in the urine, other porphyrins may be present, and the porphyrin composition of the stool is highly variable and nonspecific.

  • Quantitative porphyrins from 24-hour collections of urine and stool: Note that no protoporphyrin is detected in urine in erythropoietic protoporphyria (not a hepatic porphyria) despite high serum and erythrocyte porphyrin levels.

  • If further clarification is needed to distinguish between acute intermittent porphyria, porphyria cutanea tarda, or variegate porphyria, the Porphyria DNA Testing Laboratory at Mt. Sinai School of Medicine (New York) can be asked to perform DNA testing from a single blood sample. Issues of insurance coverage need to be considered, however, and genetic testing should be reserved for patients where additional clarification is necessary. As with other genetic tests, special privacy and counseling requirements must be met (POC for testing, contact porphyria@mssm.edu).

  • If DNA confirmation has occurred, further DNA testing of family members can be done to determine whether precautions should be taken to avoid exacerbating attacks including the avoidance of potentially risky medications [14] and fasting.

  • Liver function tests (eg, SGOT):

    • Refsum disease: Results may be abnormal with advanced phytanic acid storage.

    • Porphyrias: Findings are usually normal except in porphyria cutanea tarda, especially when liver is enlarged clinically, or in advanced erythropoietic protoporphyria with chronic secondary hepatic failure (recall that erythropoietic protoporphyria is erythropoietic, not hepatic in etiology).

    • Differentials to Refsum disease: LFT results should be abnormal in Niemann-Pick disease and metachromatic leukodystrophy with hepatosplenomegaly.

  • CBC count with differential should be checked. Refsum disease: Results are normal. Porphyrias: Results are normal, but leukocytosis may be evidence of generalized systemic stress during acute attacks. Differential for porphyrias: Hypochromic normocytic anemia with basophilic stippling is seen in chronic lead poisoning.

  • When porphyria is suspected in a patient without a family history, lead levels from blood or 24-hour urine collection should be obtained to exclude lead poisoning. Erythropoietic protoporphyria, a nonhepatic porphyria, should be considered when no clear family history is elicited.


Imaging Studies

Plain radiography of the hands documents skeletal deformities in Refsum disease.

An MRI has 2 indications in the work-up of porphyria: (1) To exclude glioma when a patient with porphyria also has seizures in latent or acute periods; confluent cortical signal intensities may occur during acute attacks and then resolve completely when attacks are over; (2) To exclude multiple sclerosis (periventricular lesions are typical) within the differential diagnosis of the porphyrias.


Other Tests

Electromyogram should include selective needle exam and nerve conduction exam for polyneuropathy. Both Refsum disease and the hepatic porphyrias are associated with polyneuropathy with both segmental and axonal characteristics.

For electroencephalography (EEG), perform a routine awake study to search for epileptiform tendencies that suggest a process independent of acute porphyric attacks. Localized or generalized spike and after slow wave activity observed during latent periods defines the risk (but not the severity or frequency) of seizures. Treatment is solely a clinical decision. During stupor or coma, the EEG can be used to exclude status epilepticus as a cause of obtundation. Interictal epileptiform activity observed during acute attacks has no value in diagnosing idiopathic epilepsy, since seizures at that time are likely part of the acute attack and should respond to appropriate treatment (see Treatment).

For urinalysis for metachromatic leukodystrophy, urinary screening for decreased arylsulfatase A or increased metachromatic granules may help rule out metachromatic leukodystrophy in the differential diagnosis of Refsum disease. If it is not definitive, a sural nerve biopsy can be done (see Procedures).

ECG may feature nonspecific changes in Refsum disease.



Sural nerve biopsy: If noninvasive urinary tests are not diagnostic, examination of the sural nerve for metachromatic granules and decreased arylsulfatase A activity can confirm metachromatic leukodystrophy in the differential diagnosis of Refsum disease

Lumbar puncture may be done to exclude multiple sclerosis and Guillain-Barré syndrome.

Elevated cerebrospinal fluid (CSF) protein: Although characteristic of Guillain-Barré syndrome, this finding may be present with prominent polyneuropathy in either porphyria or Refsum disease.

Multiple sclerosis panel: Positive oligoclonal banding, increased gamma globulin, and increased immunoglobulin G synthesis rate confirm the diagnosis of multiple sclerosis. Myelin basic protein also may be present and supports the diagnosis.


Histologic Findings

Refsum disease at autopsy reveals widespread abnormal lipid stores (specifically phytanic acid) in neural and visceral tissues (eg, liver, heart, kidney).

Hepatic porphyrias at autopsy reveal no abnormal storage; liver tissue by light and electron microscopy is normal except in erythropoietic protoporphyria, which may be associated with hepatic failure (ironically, hepatic porphyrias are not associated with hepatic failure). Special fluorescent techniques can be used to document fluorescing porphyrins.