Depressive symptoms delayed but subsequently led to the diagnosis of transthyretin amyloidosis: a case report

Abstract

Transthyretin amyloidosis is a rare disorder caused by the accumulation of misfolded transthyretin amyloid in organs. The symptoms can include neuropathy, cardiomyopathy, nephropathy, depression and cognitive decline. Because of the non-specificity of symptoms, it usually takes considerable time to diagnose, which delays specific therapy and leads to a worse prognosis. Our case highlights the psychological symptoms of this disorder that initially delayed diagnosis, and later helped to reach the correct diagnosis. We report the case of a man who presented with weakness of limbs, dizziness, vomiting, social withdrawal, loss of interest, reduced energy and difficulty concentrating. Different specialist evaluations failed to identify a cause, and the symptoms were attributed to depressive disorder. After psychiatric hospitalization to rule out depression as a possible cause, the patient was transferred to an internal medicine clinic where additional diagnostics led to a transthyretin amyloidosis diagnosis. Early-stage transthyretin amyloidosis is difficult to diagnose owing to its non-specific symptoms, but timely treatment is necessary to improve the disease course and outcome. With reference to this case, we emphasize that psychological symptoms in somatic illnesses can both delay and facilitate diagnosis of underlying disease.

Introduction

Research literature and clinical practice indicate that almost all chronic somatic diseases, especially those affecting the central nervous system, are associated with a substantially increased incidence of psychological symptoms, including anxiety, depression and cognitive decline. ¹ However, these psychological symptoms usually remain undetected because patients and physicians pay insufficient attention to them; this often leads to poorer quality of life and worse prognosis of the patient’s overall health condition. ²

It is important to note that some conditions involve a combination of various somatic and psychological symptoms that may all be hastily and incorrectly attributed solely to a mental disorder, leading to a delay in the correct diagnosis of somatic illness and loss of valuable time for the treatment of the underlying disease. Somatic disorders that are often initially misdiagnosed as depression include hypothyroidism, meningiomas, anemia, diabetes, and cancer. ³ This case report provides a good example of the attribution of a variety of somatic symptoms exclusively to a mental disorder owing to the failure to recognize and diagnose the underlying somatic disease.

Transthyretin amyloidosis (ATTR) is a rare multisystem, often fatal, disease caused by the accumulation of misfolded transthyretin аmyloid fibrils in various organs and tissues.^4,5 This disease occurs in two forms. The first form is caused by a mutation in the transthyretin gene, which causes hereditary ATTR (ATTRv); the second form is associated with aging, which causes wild-type ATTR (ATTRwt). ⁶ Although until recently it was thought that ATTRv was characterized by predominantly neuropathic symptoms, advances in diagnostics have indicated that cardiomyopathy can be a dominant feature in this type of amyloidosis. ⁷ In contrast, it was previously thought that ATTRwt classically manifests by cardiomyopathy in older age, but recent studies suggest that some patients with ATTRwt present with tenosynovial tissue complications, particularly carpal tunnel syndrome, and emphasize the association between wild-type transthyretin deposition in the ligaments and spinal canal stenosis. ⁸ Additionally, patients with ATTRwt frequently present with signs of nephropathy and gastrointestinal symptoms, as well as fatigue and weight loss. All these signs and symptoms are related to multisystem amyloid deposition.^9,10 Recent research suggests that amyloid also accumulates in the central nervous system, causing psychological symptoms that always have negative effects on patients’ quality of life.^11,12

A small number of studies have examined psychological symptoms in patients with ATTR, and have found that anxiety, depression and cognitive dysfunction are common, reported in nearly 50% of patients.^{13 –16} Several studies have shown that greater disease severity is associated with higher levels of anxiety, depression and cognitive dysfunction.^14,16 These symptoms are considered to be related to both the deposition of amyloid in the central nervous system and the known psychological effects of progressive and disabling disease on mental health.^{13 –16}

It is important to note that treatments are available that can slow the progression of ATTR and improve the function of affected organs. These therapies can stabilize the disease and reduce mortality. Although liver transplant used to be the treatment of preference, recently, the focus has switched to the transthyretin protein stabilizers diflunisal and tafamidis, which can delay the progression of the illness. ¹⁷ Additionally, gene silencing medications such as patisiran and inotersen have resulted in up to 80% reduction in transthyretin production, leading to improvements in neuropathy, cardiac dysfunction, and functional outcomes.^{18 –20} Considering that this type of amyloidosis is very rare and manifests with a variety of symptoms, correct and timely diagnosis requires substantial expertise; however, the frequent diagnostic delay and underdiagnosis of ATTR is a global problem. ²¹

In their clinical work, physicians often do not consider the clinical entity of ATTR because of workload pressures, lack of time and the often non-specific clinical picture of amyloidosis. Importantly, the median interval from initial symptoms to diagnosis is estimated to be more than 3 years. ⁹ We emphasize this delay given the fact that correct diagnosis and timely treatment of ATTR is essential for the potential efficiency of treatments. ²² If patients are not treated in the early stages, the course of the disease is substantially worse: without therapy, the average life expectancy of a patient with ATTR is approximately 10 years from symptom onset. ²³

Case description

The presentation of this report follows the CARE guidelines ²⁴ and all patient details have been deidentified. The sources of data on this case comprised information received from the patient and his family, as well as medical records from the hospital where the patient is being treated. Patient P was admitted to the Psychiatry Clinic at the University Clinical Center of Vojvodina in Novi Sad, Serbia, in June 2024. The reason for psychiatric hospitalization was a progressive deterioration of the patient’s overall health condition with predominantly depressive symptoms and cognitive decline.

The patient was a young man in his early 20s who was brought to the university hospital accompanied by his mother. The mother reported the patient’s symptoms, which included limb weakness, dizziness, vomiting, weight loss, social withdrawal, loss of interest, reduced energy, and difficulty concentrating. All these symptoms had gradually emerged over the last 5 years, particularly within the last year. The mother associated the emergence of all the patient’s symptoms to his experience of stressful life events, including the breakup of an emotional relationship at the time of symptom onset. Over the last few years, the patient had been repeatedly examined by his general practitioner from the regional health center because of these symptoms. Using basic diagnostic procedures, the patient’s physician concluded that the patient did not have any specific somatic diseases. The physician and the patient’s family attributed his condition to mental health issues, and therefore believed that his symptoms would improve spontaneously and that there was no need for a psychiatric consultation. However, over time, the patient became less mobile, did not leave his room, lost more than 20 kg in weight and neglected all his social activities. On the day of his admission to the psychiatric clinic, the patient lost consciousness for a few seconds while he was still at home. This prompted his mother to call an ambulance and to take him to the emergency department at the university hospital. On the initial physical examination, the emergency medicine specialist noted symmetrical weakness and hypotrophy of limbs, cachexia, hypotension and tachycardia. A neurological examination was performed, and the patient’s Neuropathy Impairment Score, which is used to assess muscle weakness, decrease of muscle stretch reflexes and sensation loss, was 30 (score range: 0 to 150). ²⁵ Neuropathy was found to be lower limb-predominant, length-dependent and symmetrical, with the involvement of the sensory, motor and autonomic peripheral nerves. ²⁵ Basic laboratory blood tests showed reduced hemoglobin values (105 g/L) and increased levels of urea and creatinine, leading to the diagnosis of anemia and stage 2 chronic kidney disease. An abdominal ultrasound and brain computed tomography scan were also performed, but the results did not indicate any somatic disease.

After the initial diagnostics and examination, both the neurologist and internal medicine specialist concluded that there were no symptoms of any acute somatic illness that required hospital treatment, and that the patient should be referred to a psychiatrist. In the absence of diagnostic confirmation of somatic disease, the patient’s general condition was attributed to his psychological state, and he was accordingly referred to the psychiatric clinic.

On admission to the psychiatric clinic, additional detailed data were obtained that indicated that the patient had experienced a gradual general physical and mental deterioration over approximately the last 5 years. Namely, the patient’s mother stated that the patient had gradually neglected his social relationships, showed reduced interest, and had depressive symptoms for more than 2 or 3 years. During the last year, the patient had shown a rapid deterioration in his general and mental condition. He stopped leaving his room, ate very little, often vomited, lost more than 20 kilograms, experienced dizziness, and became completely disinterested and lethargic. During his 3-day psychiatric hospitalization, the presence of moderate depressive symptoms were assessed using the Beck Depression Inventory, ²⁶ on which he obtained a score of 20, indicating moderate depression. The presence of mild cognitive impairment was assessed using the Montreal Cognitive Assessment, ²⁷ on which he obtained a score of 23, indicating mild cognitive impairment. His observed symptoms led to the prescription of the antidepressant fluoxetine and a low dose of the atypical antipsychotic olanzapine. After detailed psychiatric and physical examinations, it was concluded that depressive disorder could not be responsible for the patient’s diverse symptoms, including his somatic symptoms. The patient was transferred to an internal medicine clinic so that further diagnostics and nutritional therapy could be carried out. He was subsequently transferred to a neurology clinic. An echocardiogram showed increased left ventricular wall thickness, and electromyoneurography showed severe sensorimotor polyneuropathy. Brain magnetic resonance imaging showed no structural changes.

The observed multisystemic symptoms, including progressive polyneuropathy, myocardiopathy and nephropathy, suggested some kind of hereditary disease. Therefore, the treating physicians asked the patient’s relatives for more information. The patient’s mother then revealed that his uncle, who lived abroad, had been treated for ATTR more than 10 years ago. This information prompted the physicians to perform a specific test for ATTR, which was positive. The genetic mutation p.(Phe84Ser), which is a known pathogenic missense mutation in the transthyretin gene, was detected in a heterozygous state. After the proven but delayed diagnosis of ATTRv, symptomatic treatment was continued and specific treatment with the small interfering RNA vutrisiran was initiated after obtaining the patient’s consent.

Discussion

This case report indicates that diagnostic delay and misdiagnosis of ATTR remain unacceptably common, as highlighted in previous studies. ⁵ It is important to emphasize these problems, which can hinder treatment despite the availability of novel disease-modifying therapies for ATTR, such as transthyretin stabilizers and gene silencers like small interfering RNA or antisense oligonucleotide, which, if applied in a timely manner, can lead to a more favorable disease course and better patient quality of life. The non-specificity of symptoms and the limited knowledge of medical professionals contribute to low awareness and subsequent underdiagnosis of this serious medical condition. ²⁸ Therefore, when considering diagnostic possibilities in a patient with non-specific psychiatric symptoms, it is necessary to obtain a detailed family history and to perform a comprehensive neurological examination. In recent years, the incidence of ATTR has increased; this may be related to slightly better recognition of the condition, but also definitely reflects the availability of tests that can confirm the presence of the disease. ²⁹

Transthyretin amyloid is usually deposited in the peripheral nerves, heart, kidneys, eyes and central nervous system, and its accumulation causes a variety of symptoms that include sensory, motor and autonomic neuropathy; cardiomyopathy; nephropathy; ophthalmopathy and various symptoms of mental health impairment. ³⁰

The most common psychological symptoms, as observed in our patient, are depression and cognitive impairment.^13,16 The severity of these psychological symptoms can vary and is associated with the intensity of the somatic symptoms of the underlying disease as well as the age of the patient.^14,16 However, it is very difficult to determine whether these symptoms are just a consequence of chronic progressive disease and aging or whether they are a direct product of the underlying disease caused by the accumulation of amyloid in the central nervous system. ³¹

What makes this case report remarkable and unique is that the patient’s psychological symptoms and consequent psychiatric hospitalization led to the diagnosis of the underlying disease. Namely, after a long period in which the causes of the various somatic symptoms could not be determined, the worsening of the patient’s overall health condition led to the need for examination and diagnostics in a hospital emergency department. At that time, the on-duty internist and neurologist attributed the somatic symptoms of fatigue, loss of energy, limb weakness, and weight loss to mental disorder. This led to psychiatric hospitalization and a more detailed medical approach to examining all the patient’s symptoms and general condition, after which a correct diagnosis was made.

The frequent absence of a specific set of symptoms and specific laboratory findings for ATTR, as in this case, leads to delayed diagnosis of the underlying disease. Physicians then often attribute various symptoms of somatic illness to the consequences of depression, and waste valuable time that could be used reaching a diagnosis and treating the underlying somatic disease.

Conclusion

We considered it important to report this case of ATTRv, which mainly presented with weakness, weight loss, and depression. The non-specificity of the symptoms, as well as the insufficient experience and knowledge of the attending physicians, were challenges in reaching a timely diagnosis.

This case report emphasizes the importance of considering a diagnosis of ATTR in patients who exhibit a combination of neuropathy, cardiomyopathy and gastrointestinal symptoms, with or without psychological symptoms. Timely diagnosis and initiation of specific treatment can prevent irreversible organ damage and possibly improve the course and outcome of the disease.