Analysis of the Instestinal Microbiome of Patients With Transthyretin Amyloidosis

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Brief Title

Analysis of the Instestinal Microbiome of Patients With Transthyretin Amyloidosis

Official Title

Analysis of the Intestinal Microbiome of Patients With Transthyretin Amyloidosis

Brief Summary

      Amyloidosis is a serious systemic disease. Cardiac involvement has a great impact on
      prognosis and can occur in its three main forms: acquired monoclonal light chain, hereditary
      transthyretinal and senile form. The physiopathogenesis basically results from the deposition
      of an abnormal protein (amyloid) with toxic properties to the myocyte. The scope of this
      study will be a hereditary transthyretinal amyloidosis (hATTR). It is known that amyloidotic
      cardiomyopathy due to transthyretin deposit is an underdiagnosed cause of heart failure in
      adults, being an important differential diagnosis of diseases that manifest with increased
      myocardial thickness, such as hypertrophic cardiomyopathy or myocardial hypertrophy that
      accompanies the different degrees of aortic valve stenosis.

      The human gut microbiota is immensely diverse. It is estimated at around 100 trillion
      microorganisms, including bacteria, fungi and viruses. The microbiota of each individual is
      unique and determined by genetic factors such as age, type of delivery, use of antibiotics
      and diet. Recent data point to the hypothesis that the resilience of the intestinal
      microbiota plays a role in the process of disease development and health restoration.
    

Detailed Description

      The scope of this study will be hereditary transthyretinal amyloidosis (hATTR). It is known
      that amyloidotic cardiomyopathy due to transthyretin deposition is an underdiagnosed cause of
      heart failure in adults, being an important differential diagnosis of diseases that manifest
      with increased myocardial thickness, such as hypertrophic cardiomyopathy or the myocardial
      hypertrophy that accompanies the different degrees of aortic valve stenosis.

      The transthyretin protein is synthesized and secreted into the bloodstream mainly by the
      liver. Other organic sites also produce and secrete it in smaller amounts. The choroid plexus
      produces and releases transthyretin in the cerebrospinal fluid, while the cells of the
      pigmented retinal epithelium are also capable of producing and releasing it into the vitreous
      body. Formerly called prealbumin, transthyretin is composed of four monomers that circulate
      in tetrameric form. It has the main function of carrying retinol and thyroxine . The
      degeneration of the protein tetramer and its deposition in the different fluids in which it
      is present determine the clinical dysfunction and the specific phenotypes of ATTR.

      The gene that decodes the transthyretin protein (TTR) is located on chromosome 18. In ATTRh,
      alterations in the amino acid sequence destabilize the tetramer. It is conventional to
      designate genetic variants by the initials of the normal amino acid followed by their
      position in the gene and the amino acid that replaces it. Thus, the Val30Met variant
      translates that methionine is in place of valine at position 30.

      The cuminal event of the pathophysiology is the degeneration of the tetramer into monomers
      that, once denatured, infiltrate several structures in the form of amyloid fibrils. In the
      myocardium, this process causes rigidity and varying degrees of dysfunction secondary to the
      intrinsic toxicity of these fibrils and to the occupation of the interstitium.

      Clinically, ATTR can manifest itself as an autonomic polyneuropathy or as a cardiomyopathy.
      Eventually, the phenotype can involve both manifestations . Changes in the cardiac conduction
      system and arrhythmias usually precede heart failure by years.

      Within the spectrum of alterations resulting from autonomic neuropathy, different degrees of
      intestinal transit disorders may occur, manifested as diarrhea, constipation, nausea or even
      asymptomatically.

      Digestive symptoms are one of the most relevant and early clinical aspects of amyloidotic
      polyneuropathy, due to their frequency and intensity and the negative influence they have on
      the well-being of patients. Important changes in gastrointestinal motility are the main
      justification for these manifestations, being an expression of neurovegetative dysautonomia.
      Occurs: diarrhea, constipation, nausea, vomiting and feeling of gastric fullness.

      Weight loss is a progressive and important feature, usually early and constant. It may be
      linked to gastrointestinal manifestations, malabsorption or renal and digestive protein
      losses. It is one of the worst prognosis manifestations of the disease.

      The human gut microbiota is immensely diverse. It is estimated at around 100 trillion
      microorganisms, including bacteria, fungi and viruses. The microbiota of each individual is
      unique and determined both by genetic factors and by age, type of delivery, use of
      antibiotics and diet. There is evidence that such microorganisms play a fundamental role in
      food digestion, vitamin synthesis, production of short-chain fatty acids, modulation of the
      immune system and protection against infections. In healthy individuals, bacteria of the
      phyla Firmicutes and Bacterioidetes usually predominate, followed by Verrucromicrobia and
      Actinobacteria. However, the relative proportions and species present can vary widely between
      individuals and fluctuate over time, particularly during the early stages of life and during
      the evolution of certain diseases. Recent data point to the hypothesis that the resilience of
      the intestinal microbiota plays a role in the process of disease development and health
      restoration.
    


Study Type

Observational


Primary Outcome

Gut Microbiome


Condition

Amyloidosis, Hereditary, Transthyretin-Related

Intervention

collection of stools for genetic analysis

Study Arms / Comparison Groups

 Affected group by transthyretinal amyloidosis with cardiac involvement
Description:  collection of stools

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

60

Start Date

May 1, 2021

Completion Date

May 31, 2023

Primary Completion Date

May 2023

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of transthyretin amyloidosis documented by pathogenic transthyretin
             mutation;

          -  evidence of cardiac involvement on echocardiogram or MRI; amyloid deposit confirmed by
             Congo red staining or presence of myocardial scintigraphy with grade 2 or 3 uptake
             (with distant monoclonal gammopathy of uncertain significance (MGUS);

          -  in the presence of MGUS it is necessary to confirm the TTR protein in the tissue by
             immunohistochemistry or mass spectrometry. Non-consanguineous living with patients;

          -  Sign an informed consent form.

        Exclusion Criteria:

          -  Inflammatory bowel disease or persistent diarrhea for more than two weeks;

          -  Use of antibiotics and/or prebiotic or probiotic supplements in the two months prior
             to collection;

          -  Concurrent participation in other clinical studies.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

, , 

Location Countries

Brazil

Location Countries

Brazil

Administrative Informations


NCT ID

NCT05196594

Organization ID

04456582


Responsible Party

Sponsor

Study Sponsor

University of Sao Paulo General Hospital


Study Sponsor

, , 


Verification Date

October 2021