Clinical Diagnosis of Acute Porphyria

The purpose of this study is to test whether a focused questionnaire and laboratory tests can better define risk factors associated with possible genetic porphyria. The investigators hypothesize that the genetic carrier state of acute porphyria is distinctive enough that the Genetic Carrier Profile the investigators devise through this study will be useful in identifying carriers of genetic porphyria among the large population with undiagnosed abdominal pain.

Study Overview

• Status: Completed
• Conditions: Acute Intermittent Porphyria (AIP); Hereditary Coproporphyria (HCP); Variegate Porphyria (VP)

Detailed Description

The porphyrias are a group of genetic diseases caused by disturbances in the formation of heme, an essential component of hemoglobin and other proteins, leading to either acute (neurologic) and/or chronic (cutaneous) symptoms. Acute porphyria is often difficult to diagnose because symptoms may not be specific and, unless the patient is in an active attack, laboratory values typically may not be useful for diagnosing porphyria. The purpose of this study is to test whether a focused questionnaire and laboratory evaluation tool can better define risk factors associated with possible genetic porphyria. The goals of this study are:

• To determine the presence and number of abnormal lab tests and porphyria-like symptoms in adult family members of the first person in a family who has been diagnosed with a disease of acute porphyria, 50% of whom are expected to carry the same genetic defect of the index case.
• To devise a Genetic Carrie Profile that could be used to screen people in whom the diagnosis of porphyria is being considered.
• To test the Profile in patients with symptoms suggestive of HCP and/or urine tests showing some elevation of porphyrins.
• To explain other possible causes of minor increases in porphyrin levels in patients with recurrent abdominal pain who have not been diagnosed with porphyria

• Study Type: Observational
• Enrollment (Actual): 148

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • UAB Porphyria Center, University of Alabama at Birmingham
  • California
    • San Francisco, California, United States, 94143
      • UCSF Porphyria Center, University of California at San Francisco
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Porphyria Comprehensive Diagnostic & Treatment Center, Mount Sinai School of Medicine
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University School of Medicine
  • Texas
    • Galveston, Texas, United States, 77555
      • UTMB Porphyria Center, University of Texas Medical Branch
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Porphyria Center, University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Group 1:

Individuals who are first-degree relatives of a patient with one of the acute porphyrias (AIP, HCP, VP). They will complete questionnaires and laboratory tests, including genetic testing for porphyria. The data will be used to develop a clinical profile for the risk factors associated with the genetic carrier state.

Group 2:

Subjects who possibly have acute porphyria, but do not have a confirmed diagnosis based on genetic testing. They will serve to test the validity of the clinical index derived from Group 1.

Group 3:

Patients who have been seen by one of the Porphyria Consortium physicians/investigators 10 or more years ago, but were not given a diagnosis of porphyria. They will complete a questionnaire to determine whether they received a porphyria diagnosis, or another diagnosis that might explain the initial presentation.

Description

Group 1 Inclusion Criteria:

• Be 15 years of age or older
• Be a first-degree relative (child, sibling, parent, or grandparent) of an individual with genetically proven acute porphyria (AIP, HCP or VP)
• Not have had any previous genetic testing for acute porphyria

Group 2 Inclusion Criteria:

• Be 15 years of age or older
• Have a history of suggestive clinical features, such as abdominal, back or limb pain, recurrent nausea lasting days, reaction to medications, psychiatric history, or sun sensitivity.
• An increase in urinary, fecal or serum porphobilinogen (PBG) and/or porphyrins

Groups 1 and 2 Exclusion Criteria:

• Have previously had genetic testing for acute porphyria
• Have a history of "alarm" symptoms, such as anemia, unintentional weight loss, signs of GI (gastrointestinal) bleeding, or dysphagia (difficulty in swallowing).

Follow Up Sub-Study (Group 3) Inclusion Criteria:

• Have been seen by one of the Porphyria Consortium physicians/investigators 10 or more years prior to study initiation
• Had a slight increase in porphyrins during the initial visit
• Not given a diagnosis of porphyria at the time of the visit

Follow Up Sub-Study (Group 3) Exclusion Criteria:

• You have been seen by the Porphyria Consortium physician/investigator less than 10 years prior to study initiation.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Group 1; Group 1 will include subjects 15 years of age or older who are a first-degree relative (child, sibling, parent, or grandparent) of an individual with genetically proven acute porphyria (AIP, HCP or VP), and have not had any previous genetic testing for porphyria themselves.
Group 2 (Not Yet Enrolling); Group 2 will consist of subjects 15 years of age or older who have a history of clinical features suggestive of acute porphyria, such as such as abdominal, back or limb pain, recurrent nausea lasting days, reaction to medications, psychiatric history, or sun sensitivity, and an increase in urinary, fecal or serum porphobilinogen (PBG) and/or porphyrins.
Group 3; Subjects in Group 3 will participate in the "Follow Up Sub-Study." This group will include individuals who have been seen by one of the Porphyria Consortium physicians/investigators for suspicion of porphyria 10 or more years prior to study initiation, but were not given a diagnosis of porphyria at the time of their initial visit.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of positive biochemical features by first-line testing in subjects suspected of being a genetic carrier of acute porphyria	All subjects will be assessed for any elevation of quantitative urine porphobilinogen (PBG).	Assessed once at baseline visit for all subjects
Presence of positive biochemical features by second-line testing in subjects suspected of being a genetic carrier of acute porphyria	All subjects will be assessed for any elevations of fractionated quantitative urine porphyrins.	Assessed once at baseline visit for all subjects
Presence of positive biochemical features by second-line testing in subjects suspected of being a genetic carrier of acute porphyria	All subjects will be assessed for any elevations and levels of fractionated quantitative fecal porphyrins.	Assessed once at baseline visit for all subjects
Clinical features suggestive of the acute porphyria carrier state	Through a focused questionnaire, we will determine the typical duration of pain attacks.	Assessed once at baseline visit for all subjects
Acute porphyria genetic carrier state	All subjects will undergo DNA analysis to detect a mutation in the HMBS, CPOX, or PPOX genes, respectively.	Assessed once at baseline visit for all subjects
Other possible causes of mildly elevated porphyrins and recurrent pain	Participants in the Follow-up Sub-study section of this protocol will be interviewed concerning other possible causes of mildly elevated porphyins and recurrent pain. These will be patients previously seen by the investigator who were deemed not to have porphyria.	Assessed once during a one-time telephone or in-person interview
Presence of heavy metals	All subjects will undergo a blood test to screen for the presence of heavy metals as a cause for minor elevations of porphyrin levels.	Assessed once at baseline visit for all subjects
Validity of Genetic Carrier Profile	The biochemical and clinical features of genetically proven but asymptomatic HCP will be tabulated and compared to subjects who are not genetic carriers. Its accuracy in predicting risk factors for HCP will be tested in subjects in Group 2.	The profile will be tested once during the baseline visit for subjects in Group 2.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of disease manifestations in genetically confirmed AIP and HCP	Subjects who are confirmed to have AIP and HCP will be assessed at annual follow up visits for the presence and frequency of porphyria symptoms.	Assessed annually for 5 years
Prevalence of HCP in a population with elevation of urine coproporphyrin and pain symptoms.	Based on the number of subjects in Group 2 determined by DNA analysis to have HCP, we will approximate the prevalence of HCP in a population with elevations in coproporphyrin and pain symptoms that are undiagnosed.	Assessed once enrollment and genetic testing of subjects in Group 2 are complete - after a 1-year recruitment and enrollment period.

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Alabama at Birmingham; Icahn School of Medicine at Mount Sinai; University of Texas; University of Utah; Rare Diseases Clinical Research Network; Carolinas Medical Center
• Investigators: Study Chair: Bruce Wang, M.D., University of California at San Francisco; Principal Investigator: Karl E. Anderson, M.D., University of Texas; Principal Investigator: Joseph R. Bloomer, M.D., University of Alabama at Birmingham; Principal Investigator: Robert J. Desnick, Ph.D., M.D., ICAHN School of Medicine at Mount Sinai; Principal Investigator: James P. Kushner, M.D., University of Utah; Principal Investigator: Herbert L. Bonkovsky, M.D., Carolinas Medical Center and HealthCare System

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: February 16, 2012
• First Submitted That Met QC Criteria: March 30, 2012
• First Posted (Estimate): April 2, 2012

Study Record Updates

• Last Update Posted (Actual): September 28, 2021
• Last Update Submitted That Met QC Criteria: September 22, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Skin Diseases; Liver Diseases; Genetic Diseases, Inborn; Skin Diseases, Genetic; Porphyrias, Hepatic; Porphyria, Erythropoietic; Porphyrias; Coproporphyria, Hereditary; Porphyria, Acute Intermittent; Porphyria, Variegate
• Other Study ID Numbers: PC7204; 1U54DK083909 (U.S. NIH Grant/Contract)