An elderly male with tingly legs and a heavy heart: Persisting with the diagnosis!

Pursuing a diagnosis despite a negative nerve biopsy report requires a strong clinical conviction. Paying attention to clinical details and a diligent review of medical records is needed to solve cases in which the diagnosis is not obvious despite numerous tests. We present once such case of an elderly man with chronic diarrhea, weight loss, and peripheral neuropathy and elaborate on a step by step basis on how the clinical thought process evolved after sifting through the reports of scan and tests done during his work up.

Introduction

We present the history of a 62-year-old patient who presented with chronic diarrhea, weight loss, and symptoms of peripheral neuropathy. He presented initially to the gastroenterologist and later to the neurologist and was extensively worked up for the above symptoms.

Case Report

A 62-year-old man presented initially with weight loss and chronic diarrhea. His weight loss was in tune of 30 kg over a period of 5 years. He had long-standing Type 2 diabetes which was well controlled with HbA1c <6% and had not had any evidence of retinopathy or nephropathy. His oral antidiabetic medications were stopped given his weight loss, and his glucose continued to remain under control. Given the extreme weight loss and chronic diarrhea, endoscopic investigations, and detailed imaging studies were undertaken which included upper, lower endoscopy, capsule endoscopy, whole body computerized axial tomography scan, fluorodeoxyglucose-positron emission tomography scan, Octreotide scan none of which delineated any neoplastic etiology.

Over the past 2 years, before the current presentation, the patient developed parasthesias of both lower limbs and orthostatic dizziness. He was admitted under the neurology team and evaluated. His clinical examination revealed orthostatic hypotension (supine blood pressure 110/70 and erect posture 70/50 mm of Hg) with a fixed heart rate of 60 beats per minute. He also had bilateral lower extremity distal motor weakness (MRC 4/5) with decreased sensation (pinprick, light sensation, and proprioception) extending from feet up to knees, with absent tendon reflexes in the lower limbs. Romberg's test was positive. Nerve conduction study showed bilateral distal multifocal sensory motor demyelination along with axonal neuropathy.

How is the autonomic testing done at the bedside?

Measurements of orthostatic blood pressure (A fixed heart rate without a compensatory increase to drop in blood pressure is a strong clue)

Heart rate response to tilt, heart rate variability with deep breathing, and changes in blood pressure with the Valsalva manoeuvre are other techniques.

What are the causes of autonomic neuropathy?

Systemic causes:

Diabetes

Amyloidosis

Sjogren syndrome

Collagen vascular disorders

Renal failure

B12 deficiency

Toxins

Infections (syphilis, Lyme, HIV, Chagas)

Sarcoidosis

Porphyria.

Primary Neurogenic causes:

Neurodegenerative disorder:

▪ Parkinson disease

▪ Lewy body dementia

▪ Multisystem atrophy (Shy–Drager syndrome)

▪ Pure Autonomic failure (Bradbuy-Eggleston syndrome)

Neuropathy:

Acute inflammatory demyelinating polyneuropathy

Paraneoplastic autonomic neuropathy

Autoimmune autonomic ganglionionopathy

Familial dysautonomia (Riley–Day syndrome).

Thyroid hormones, autoimmune antibody panel, and Vitamin B12 were normal while hepatitis and retroviral serologies were negative. Serum immunofixation electrophoresis and urine free light chains were negative for monoclonal disorders. Cerebrospinal fluid study was normal. In view of features of both peripheral and autonomic neuropathy, sural nerve biopsy was performed which showed features of both demyelinations in small nerve fibers and axonopathy. Congo red stain for amyloid was negative. It was concluded that he had diabetic peripheral and autonomic neuropathy and discharged with symptomatic measures.

3. Is amyloidosis ruled out by a negative nerve biopsy?

Congo red amyloid staining may be absent in the sural nerve and other organ biopsies in a group with late-onset organ-specific amyloidosis

It is important to consider that nerve biopsies carry the risk of a sampling error due to the focally accentuated and discontinuous distribution of amyloid deposits along the nerve axis.

He presented to the endocrine and internal medicine clinic with worsening symptoms of orthostatic hypotension, and parasthesias. His case records were carefully rereviewed. It was noted that in his previous echocardiograms, there was a consistent mention of the left ventricular (LV) hypertrophy on more than one occasion despite the absence of hypertension. His recent electrocardiogram (ECG) showed new onset left bundle branch block in comparison to a normal ECG 3 years back. A repeat two-dimensional echocardiogram showed concentric LV hypertrophy with reduced ejection fraction (45%) and global hypokinesia. Cardiac magnetic resonance imaging (MRI) showed dilated atrium, LV hypertrophy, with filling restriction of ventricles with late gadolinium enhancement (LGE) of subendocardium highly suggestive of cardiac amyloidosis [Figure 1]. On further questioning, the patient gave a history of the sudden unexpected death of his father and paternal uncle at the age of sixty, both of whom did not have any prior comorbidities.

Figure 1

(a) Long axis 4C-10 min showing diffuse sub-endocardial enhancement in hypertrophied ventricles and atria with zebra stripe appearance (b) Short axis 2CH-10 min showing sub-endocardial bi-ventricular enhancement (c) 4CH cine Diastole imaging shows thickened inter-atrial septum with pericardial effusion (arrow) (d) Cine 4C showing bi-atrial dilatation in systole (star)

4. What are the imaging characteristics of cardiac amyloidosis?

ECG shows low voltage complexes in the setting of an echo report of LV hypertrophy

Increased LV wall thickness with evidence of diastolic dysfunction is the earliest echocardiographic abnormality, and right ventricular diastolic dysfunction can also occur

Progressive LV wall thickening results in a nondilated or small LV cavity with systolic impairment and restrictive physiology occurs with more advanced disease

The atria become enlarged and immobile, and thickening of the mitral and aortic valve leaflets and atrial septum may be noted

Amyloid infiltration of the heart results in increased echogenicity causing a “sparkling” myocardium

Cardiovascular magnetic resonance (CMR) imaging can provide evidence strongly suggestive of amyloid cardiomyopathy, particularly a distinctive pattern of global LV LGE rarely seen in other cardiomyopathies

Technetium imaging may have a role to play specifically in transthyretin (TTR) amyloid-induced cardiomyopathy.

In view of the cardiac MRI which strongly suggested the presence of cardiac amyloid and the convincing absence of a plasma cell dyscrasia or chronic inflammatory disorder, and a suggestive family history, genetic studies for familiar amyloid polyneuropathy was carried out. A heterozygous missense variation in exon 2 of the TTR gene (chr18:29172917; G > G/A) resulting in the amino acid substitution of asparagine for serine at codon 43 (p.S43N; ENST00000237014) was noted. This S43N variant has previous been identified in a Portuguese patient with familial amyloidosis.[1] Hence, a final diagnosis of hereditary TTR-related amyloidosis (OMIM#105210) was made. The patient is being managed symptomatically with rifaximin and loperamide for his diarrhea and stockings for his legs. He has had stable neurological, cardiac status at 6 months of follow-up.

Discussion

The amyloidosis is a rare group of diseases that result from extracellular deposition of amyloid, a fibrillar material derived from various precursor proteins that self-assemble with highly ordered abnormal cross β-sheet conformation.[23] Deposition of amyloid can occur in the presence of an abnormal protein (amyloid light chain [AL] amyloidosis), in association with a prolonged excess abundance of a normal protein (Amyloid A [AA] amyloidosis and β2-microglobulin dialysis-related amyloidosis), and accompanying the aging process (senile systemic amyloidosis). Cardiac involvement occurs in up to 50% of patients with AL amyloidosis compared to <5% with AA amyloidosis.[45] In ATTR amyloidosis, the amyloid protein consists of wild-type (nonmutant) or mutated TTR. TTR is a small protein tetramer that is almost exclusively produced in the liver. Wild-type (nonmutated) TTR is responsible for senile systemic amyloidosis, the predominant feature of which is an infiltrative cardiomyopathy while TTR-associated amyloidosis due to mutations in the gene for TTR are often associated with amyloid cardiomyopathy. Some mutations are invariably associated with cardiac disease, others usually only with neurologic disease, and many have a combination of both.[6] We present a case of an elderly man with diabetes who presented with weight loss and progressive peripheral and autonomic neuropathy and despite a negative nerve biopsy for amyloidosis, persistent evaluation confirmed the diagnosis of hereditary TTR-related amyloidosis.

The TTR or prealbumin gene is located on chromosome 18, and more than 120 TTR mutations have been described, including single mutations, compound heterozygotes, and deletions.[7] Hereditary TTR amyloidosis is caused by any one of more than 100 mutations in the TTR gene.[8] Single substitutions in an amino acid of TTR can render it unstable, resulting in a tendency to misfold and produce amyloid, which commonly infiltrates the myocardium and the endoneurium.[9] Nearly, all mutant TTR gene products are amyloidogenic. Mutations have been identified in approximately 40% of the amino acids of this 127 residues single chain molecule. Different variants of the TTR gene mutations present predominantly as neuropathic, cardiomyopathic, and/or ocular (vitreous) disease, which may be familial or sporadic.

In endemic areas of Portugal, 1 of every 600 people carries a TTR gene that leads to a methionine substitution for valine at position 30 and that may result in familial amyloidotic polyneuropathy.[10] The same mutation is seen in some other countries such as Sweden and Japan.[89] Although haplotype analysis of contiguous TTR gene regions in Swedish, French, Portuguese, and Japanese carriers indicates common founders, these phenotypic differences suggest the importance of additional genetic and epigenetic factors in disease expression.[11] Isolated cardiac amyloidosis presenting virtually exclusively as late-onset (age >65) disease is more common in African Americans than Caucasians, and 3–4% of African Americans and Afro-Caribbean individuals are carriers for an amyloidogenic substitution of isoleucine for valine at position 122 (V122I). In addition, the carrier rate is >5% in some areas of West Africa. Although the prevalence of the V122I TTR variant is relatively high in these populations, it appears to have low penetrance for causing amyloid cardiomyopathy. Five TTR mutations (Gly30, Arg 53, Ser64, His69, Cys 114) have been associated with clinically significant central nervous system involvement, manifesting as leptomeningeal involvement, dementia, cerebellar dysfunction with ataxia, or cerebral hemorrhage.[212]

The clinical manifestations vary, depending on the particular substitution, but result either in neuropathy, cardiomyopathy, or both. A common mistake is to attribute ventricular wall thickening in these patients to hypertensive heart disease, but the degree of LV thickening (commonly >15 mm) is usually disproportionate to the degree of hypertension, and right-sided signs of heart failure (uncommon in hypertensive heart disease) are frequently present due to concomitant right ventricular infiltration. The substitution of methionine for valine at codon 30 (Val30Met), endemic areas such as Portugal, Northern Sweden, and Japan, and most often presents with a lower extremity sensorimotor peripheral neuropathy (known as familial amyloid polyneuropathy). Although cardiac involvement occurs and echocardiographic manifestations may not be distinguishable from AL amyloidosis, these patients generally have much less severe myocardial disease and better survival than those with AL amyloidosis.[1314] There appears to be a bimodal age of onset in this mutation, with early onset (third and fourth decade) presenting with peripheral neuropathy and minimal cardiac infiltration except for conduction system disease and late onset disease (sixth decade) presenting predominantly as an infiltrative amyloid cardiomyopathy. In contrast, the Thr60Ala mutation, first described in the Appalachian region of the United States, and other less common mutations[151617] are associated with a severe infiltrative cardiomyopathy, often with minimal neuropathy. Individuals with THr60Ala typically present at 50–60 years of age.[18]

Amyloid deposition initially present around endoneurium and around nerve blood vessels with progression of disease nerve fiber density decreases and invasion of endoneurial blood vessel by amyloid leading to its destruction, presenting as initially small fiber followed by large and autonomic dysfunction. Biopsy of peripheral nerve specimens, salivary glands or abdominal fat can be negative, and hence the establishment of diagnosis depends on TTR gene mutation detection in such cases.[19] CMR imaging can provide evidence strongly suggestive of amyloid cardiomyopathy, particularly a distinctive pattern of global LV LGE rarely seen in other cardiomyopathies. CMR appears to be more sensitive for cardiac amyloid deposition than echocardiography, as CMR LGE may be seen in patients with amyloidosis with normal LV wall thicknesses. Preliminary studies of the predictive value of LGE in patients with suspected cardiac amyloidosis have yielded sensitivities of 86–88% and specificities of 86–90%.[2021]

Liver transplant is definitive line of management, aim being prevention of additional amyloid deposition produced by TTR mutant. Liver transplant is better in patient with Val30Met mutation of TTR gene mutation with median survival rate >20 years.[2223] The main factor determining the outcome after liver transplant is cardiac dysfunction. The use of flufenamic acid, which inhibits the dissociation of mutant TTR tetramer, is another investigational therapeutic approach. Two more molecules diflunisal (NCT1435655) and tafamidis meglumine (NCT01435655) are undergoing clinical trial. Both increases stabilizer of TTR tetramers in pivotal phase randomized double trail.[24]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.