7204 - Clinical Diagnosis of Acute Porphyria

Overview

Status: Recruiting
Keywords: Acute Porphyria , Hereditary Coproporphyria , HCP
IRB Number: 00055502
Specialty: Hematology/BMT
Sub Specialties:

Brief Summary

Primary Objectives:

a.  To determine the prevalence of abnormal lab tests and porphyria-like symptoms in adult family members of an index case of Hereditary Copropophyria (HCP), and Variegate Porphyria (VP) - who are confirmed carriers of the patient's genetic defect; based on these data, to devise a clinical index for the likelihood of the HCP genetic carrier state.

b.  To test the validity of the index prospectively in patients with a possible diagnosis of HCP based on an elevated urinary coproporphyrin and the major features of the index. A control group will consist of sex- and age matched individuals who are not selected by symptoms but have elevated urinary coproporphyrin.

c.  To elucidate other possible causes of minor increases in porphyrin levels in patients with recurrent abdominal pain who have not been diagnosed with porphyria.

Secondary Objective:

To assess the frequency of disease manifestations in genetically confirmed AIP and HCP; to assess the prevalence of HCP in a population with elevation of urine coproporphyrin and pain symptoms.

Detailed Description

All types of porphyria represent disturbances in the formation of heme, an essential component of hemoglobin and cellular cytochromes. Each is due to a hereditary or acquired defect in one of the enzymes of heme synthesis. The enzyme defect restricts the flow of heme precursors, with spillover of intermediates to excretory routes. The porphyrias are divided into acute (neurologic) and chronic (cutaneous) forms. In the acute form, neuropathic symptoms predominate, including ileus, visceral pain, seizures, motor neuron disease and (when advanced) respiratory paralysis. Many genetic carriers have no symptoms. Attacks are induced classically by medications that increase the demand for heme production. In the cutaneous types, porphyrins accumulate in the skin causing photosensitivity. Hereditary coproporphyria (HCP) involves a mutation in coproporphyrinogen oxidase, which catalyzes the conversion of coproporphyinogen to protoporphyrinogen. People with active HCP display features of both acute and cutaneous porphyria; photosensitivity may occure in the absence of acute symptoms in some individuals. HCP appears to be expressed clinically less frequently than is acute intermittent porphyria. Its prevalence in the American population is unknown, but i may be relatively common. In asymptomatic individuals, urinary and fecal coproporphyrin generally are mildly elevated, although it is unclear if all genetic carriers exhibit even these markers. The biochemical evaluation is complicated by the fact that excess urinary coproporphyrin occurs also in a large number of health conditions unrelated to porphyria -- most commonly liver disease, but also neurological and hematological conditions (13). This is a major cause of confusion for patients and leads to much misdiagnosis.

Principal Investigator: Charles Parker
Department: Hematology
Co Investigator:

Contact Information

Name:Jeanette Davis
Phone: 801-587-7525
Email: jeanette.davis@hsc.utah.edu

Inclusion Criteria

The clinical and biochemical signs of acute porphyria appear only after puberty. Therefore the study participants in all groups will be adults, although participants age 15-17 may be considered, with parental consent.

 All research subjects must be capable of understanding, and in agreement with, the purposes of the study, which will include genetic testing.

 Part 1:

Group 1:  First-degree relative of an individual with a disease-causing mutation in either HMBS or CPO, who has never had genetic testing.

 Part 2:

Group 2:

1. Clinical features:

        a.    A history of “possible porphyria” based on symptoms and biochemical findings. This group will be analyzed as two subgroups, defined as having, or not having, symptoms that are “highly associated” with the genetic carrier state.

2. Biochemical findings:

         For AIP

         a.     Increased urinary or serum PBG

                  i. Urinary PBG >2 fold relative to the ULN for the testing lab (mg/24 hours or mg/g creatinine)

                  ii. Serum PBG >2 fold increased relative to ULN of the testing lab (ug/dL)

           For HCP

           a.     More than 1.5-fold increased urine coproporphyrin relative to the ULN for the testing lab (mcg/24 hours or mcg/g creatinine)

           b.     Normal or only slight increases in fecal porphyrins.

 Follow Up Sub-Study:

  1. Have been seen by the investigator 10 or more years prior to study initiation.
  2. Slight increase of porphyrins during initial visit

             a. For AIP:

                  i.  Increased urinary or serum PBG

                  1. Urinary PBG <2 fold relative to the ULN for the testing lab (mg/24 hours or mg/g creatinine)

                  2. Serum PBG <2 fold increased relative to ULN of the testing lab (mg/dL)

              b. For HCP:

                  i. Less than a 2-fold increase urine coproporphyrin or uroporphyrin relative to the ULN for the testing lab (mcg/24 hours or mcg/g creatinine)

3. Not given a diagnosis of porphyria at the time of that visit

Others who may be enrolled

Patients with evidence of dual enzyme deficiencies, with bone marrow disorders and expansion of a clone of cells carrying an enzyme mutation, other neoplastic disorders causing porphyria, or with porphyrias that based on current knowledge do not clearly fit with the types described above. 

Exclusion Criteria

For Groups 1 and 2:

1. We will exclude cases that previously have had genetic analysis for porphyria, with the exception of the index cases of Group 1.

2. Patients with a history of “alarm” symptoms (anemia, unintentional weight loss, signs of GI bleeding, dysphagia) will be excluded, as determined by the investigator.

For Follow Up Sub-Study:

We will exclude patients who have been seen by the investigator less than 10 years prior to study initiation.