Short summary

Cardiac amyloidosis (CA) is a disease where misfolded proteins deposits on the heart which may cause heart failure and ultimately death. Retrospective studies have shown that a large number of CA-patients have had surgical treatment for carpal tunnel syndrome (CTS).

We want to invenvestigate the frequency of amyloid deposits by histological examination of tissue from the carpal tunnel of 100 consecutive patients undergoing surgical treatment for CTS. 

This will hopefully lead to early diagnosis of patients with CA.

Rationale

Carpal Tunnel Syndrome (CTS) is a condition associated with pain, paraesthesia and weakness of hand muscles including the first three- and radial half of the fourth- digit. The syndrome is believed to be caused by compression of the median nerve as it passes through the carpal tunnel. 

CTS is the most frequent entrapment neuropathy. It is believed to develop due to an increased pressure within the intracarpal tunnel. Recent investigations have reported that 7-34% of the CTS patients have varying degrees of amyloid deposits in the teno-synovial tissue which may lead to increased pressure in the carpal tunnel.

CTS is treated by surgical decompression of the carpal tunnel. Currently histological examination of tissue from the carpal tunnel or subcutaneous tissue is not part of the surgical procedure.

Amyloidosis

Amyloidosis is a generally used terminology to describe extracellular deposits of misfolded proteins which have a characteristic histological appearance.

There are several subtypes and causes of amyloidosis including senile forms, hereditary conditions, clonal plasma cell disorders, chronic renal failure in addition to inflammatory diseases.

Transthyretin (TTR) amyloidosis is the most frequent subtype of amyloid identified in teno-synovial tissue of patients with CTS. TTR amyloidosis is most frequently diagnosed in elderly individuals, especially males > 70 years of age and.

Besides being a cause of CTS, wtTTR may accumulate in the myocardium and result in bi-ventricular hypertrophy, restrictive filling patterns, atrial-ventricular conduction defects (AV-block), and supraventricular arrhythmias (SVT). Thromboembolic complications are common and in advanced cases, patients develop pulmonary congestion, peripheral edema, liver enlargement and ascites. Surprisingly, a recent study showed that up to 13% of patients with symptoms of heart failure and preserved systolic function had cardiac wtTTR amyloidosis as the cause of their condition.

Currently there is no causal therapy for cardiac wtTTR amyloidosis. Therefore, medical therapy aims to relieve symptoms of heart failure and prevent thromboembolic episodes 

Very rarely, TTR amyloidosis is hereditary (mTTR) and caused by mutations in the gene for TTR. 

Recent retrospective studies have reported that up to 25% of patients with cardiac wtTTR and mTTR amyloidosis had surgery for CTS between five and nine years ahead of their cardiac diagnosis. 

However, no knowledge is currently available on the frequency of patients who at the time of surgical treatment for TTR induced CTS also have cardiac- or other systemic- amyloid deposits. 

Amyloid light chain (AL) amyloidosis, is caused by plasma cell dyskrasia or B-cell malignancies. AL amyloidosis is a common systemic amyloidosis with an annual incidence of about 1 per 100,000 and is primarily deposited in myocardial and renal tissue. The prognosis is adverse, particularly if heart failure develops. However, new therapies are effective and has improved prognosis in patients without cardiac involvement. Thus, early diagnosis is crucial. 

Aims

1. To investigate the frequency of amyloid deposits by histological examination of tissue from the carpal tunnel of 100 consecutive patients undergoing surgical treatment for CTS

a. Furthermore, to establish the subtype of amyloid in positive samples by immune electron microscopy (IEM) and mass spectrometry (MS)  

2. To perform clinical investigations of amyloid positive patients and establish if the condition is localised or additional organ systems are involved

Description of the cohort

One hundred consecutive patients >18 years of age diagnosed with CTS of unknown aetiology who receive surgical treatment for the condition will be included in the study following informed consent at the Department of Orthopaedic Surgery, Odense and Svendborg University Hospital. It is expected that 20 patients will be included per month in the study period. 

Data and biological material

Tissue for histological investigation, date of birth, sex, symptoms and diagnosis of CTS, data of diagnosis, medication, additional conditions, previous fractures of the upper extremities, extreme physical activity of the upper extremities, a family history of amyloidosis and the results of the histological investigations. Further data about the results of the clinical investigations will be collected in patients with proven amyloidosis in the carpal tunnel.

Collaborating researchers and departments

Department of Cardiology, OUH

• Professor Jens Mogensen, PhD

Co-investigators:

Department of Orthopaedic surgery, OUH

• Associate professor Hans Tromborg, PhD
• Professor Søren Overgaard

Department of Haematology, OUH

• Professor Niels Abildgaard
• Staff specialist Charlotte Toftmann Hansen, PhD

Department of Pathology, OUH

• Professor Niels Marcussen
• Consultant Hanne E. Møller, PhD
• Associate professor Aleksandra Rojek

Department of Cardiology, OUH

• 5. Consultant Redi Pecini, Phd

Department of Clinical Biochemistry and Pharmacology, OUH

• Associate professor Hans Christian Bech, PhD