Evaluating the Prevalence of Acute Hepatic Porphyria in Postural Tachycardia Syndrome

Postural Tachycardia Syndrome (POTS) affects ~3 million young women in the United States.(1)These patients have a low quality of life because of chronic presyncopal symptoms, and orthostatic tachycardia that occur while standing. POTS can be the initial presentation of an underlying illness. A substantial group of patients with POTS reported that their symptoms started after an acute illness, surgical intervention, substantial weight loss or after ingesting certain medications. These are the same triggers for acute AHP attacks.

Furthermore, the demographic characteristics of AHP overlaps with that of POTS. AHP also affects primarily young women, in their reproductive age. POTS can have a diverse presentation, some patients present with axonal autonomic neuropathy, and severe gastrointestinal symptoms which are co-morbid conditions also present in chronic AHP.

It is within this context that investigators propose to assess the occurrence of AHP in the general POTS population, identify its clinical presentation and neuro-hormonal characteristics.

Rationale and Endpoints:

• To evaluate occurrence of AHPs in POTS patients with autonomic and neurovisceral symptoms referred to a National Referral Center for the treatment of Autonomic Disorder.
• To determine the autonomic and neuro-hormonal characteristics of AHP-POTS patients compared with POTS patients

Enrollment:

This is a cross-sectional study conducted at the Vanderbilt Autonomic Dysfunction Clinic (ADC). Investigators plan to enroll patients with suspicions of POTS who are referred to the ADC for evaluation and diagnosis.

Study visit:

Single study visit.

Participants will be asked to complete an autonomic symptoms assessment questionnaire (COMPASS 31), and quality of life EQ-5D.

The following laboratory analyses will be performed:

Blood: CBC, CMP, Iron studies (Ferritin and iron studies) Urine PBG, ALA and porphyrins in a spot urine sample with results normalized to urine creatinine.

Genetic testing (Acute hepatic porphyria panel) .

Autonomic function test.

Supine and Standing plasma norepinephrine will be obtained for evaluation of neuro-hormonal changes during orthostasis.

Statistical Analyses

This is a pilot study that will estimate the occurrence of AHPs in POTS patients referred to a National Referral Center for the Treatment of Autonomic Disorders. There is no data available on the prevalence of AHPs in POTS. The prevalence of AHP is one in 6,000 in whites. [ref. Hepatol commun 2019 feb 3(2): 193-206] Given that there are overlapping of symptoms between AHP and POTS, expected that AHP would be overrepresented in POTS patients. The plan is to enroll 50 POTS patients in this pilot study.

Data Analysis Plan:

Standard graphing and screening techniques will be used, to detect outliers and to ensure data accuracy. Continuous endpoints will be assessed for normality. If normality is violated, data transformation will be applied or non-parametric analysis methods will be considered. Investigators will provide summary statistics for both continuous and categorical variables by subject groups (POTS and AHP-POTS). All hypotheses will be tested, at the level of α=0.05. SPSS (version 23.0, SPSS, Chicago, IL) will be used and the open-source statistical package R (R Core Team, 2019 for analyses.

Inclusion criteria

• Age 18 - 65 years
• Individuals having an established diagnosis of POTS defined as the presence of presyncopal symptoms for more than 6 months and orthostatic tachycardia (>30 bpm increase in HR within 10 min after assuming upright position)
• The present of one of the following criteria:

3.1 Family history of acute hepatic porphyria 3.2 Unexplained recurrent (more than one), prolonged (>24 hours) episode of severe, diffuse (poorly localized) abdominal pain AND at least TWO of the following:

• Red to brownish urine.
• Blistering skin lesions on sun-exposed areas.
• Peripheral nervous system manifestations occurring around the time of abdominal pain (i.e., motor neuropathy (paresis), sensory neuropathy (numbness, tingling, limb pain).
• Central nervous system manifestations occurring around the time of abdominal pain (i.e. confusion, anxiety, seizures, hallucinations).
• Autonomic nervous system manifestations occurring around the time of abdominal pain (i.e. hyponatremia(Na<lower limit of normal)), tachycardia, hypertension, nausea and vomiting, constipation).

Exclusion criteria

• Pregnant or breastfeeding women
• type 2 diabetes mellitus
• History of alcohol or drug abuse
• Inability to provide informed consent or comply with protocol