Severe hand pain as an extracardiac manifestation of transthyretin amyloidosis

Abstract

Transthyretin amyloidosis is a multisystemic disease caused by the aggregation of amyloid fibrils, resulting in high morbidity and mortality in the presence of cardiac involvement. Patients often experience vague symptoms that make amyloidosis difficult to diagnose. Differential diagnosis for hand pain in a patient with systemic amyloidosis is broad. We present a patient with severe hand cramping and inability to perform activities of daily living. This preceded a new diagnosis of familial amyloid cardiomyopathy. The patient was a poor responder to systemic corticosteroids, anti-inflammatories and anticonvulsant therapy. Her unique presentation gives insight into a rare but debilitating disorder and the potential link between amyloidosis and other disease processes.

Background

Transthyretin amyloidosis (aTTR) is a multisystemic disease caused by the aggregation of amyloid fibrils. aTTR consists of a familial-hereditary form and a wild-type form, previously known as senile amyloidosis.¹ The hereditary form has multiple presentations including familial polyneuropathy, cardiomyopathy and leptomeningeal amyloidosis.^{1 2} Wild-type aTTR can contribute to cardiac amyloidosis, which is sometimes resistant to liver transplantation.³ Amyloid arthropathy is a rare but debilitating disease contributing to cellular and extracellular matrix damage in articular cartilage, comparable to rheumatic diseases.^{1 2 4} Patients with systemic amyloidosis also have risk factors for the development of joint stiffness and pains due to other etiologies including neuropathy, endocrine abnormalities and crystal-induced arthritis. We present a rare case of an elderly woman whose diagnosis of cardiac amyloidosis was preceded by severe arthralgias and bilateral hand swelling.

Case presentation

This is a case of a 73-year-old woman who was prompted to call emergency medical services when she could not open her front door due to severe cramping hand pain. She presented to the hospital with bilateral hand swelling associated with burning pain for a week. This cramping pain was symmetric, affecting the fingers, palms and wrists bilaterally. Symptoms were persistent and did not worsen in the morning or after progressive use of her joints. Accompanying signs and symptoms included darkening of the overlying skin and numbness of the fingers. She also endorsed worsening shortness of breath and ambulatory dysfunction over the past several months.

The patient’s medical history was significant for diabetes mellitus type 2, hypertension and chronic kidney disease. Home medications included acetaminophen as needed, furosemide, metolazone, metoprolol, atorvastatin, warfarin, dulaglutide, linagliptin and pantoprazole. On index examination, she was sitting comfortably, her heart rate was 78 bpm, blood pressure 129/88 mm Hg and temperature was 98°F (37°C). Cardiovascular, abdominal, neurological and skin examinations were within normal limits. Lung examination revealed bilateral basilar crackles. Hand examination showed she had contractures of her bilateral metacarpophalangeal and proximal interphalangeal joints (figure 1), thenar atrophy (figure 2) and inability to perform full hand grip with a positive prayer sign (figure 3). Strength and sensation of the upper extremities were intact. Tinel’s sign was negative bilaterally. Other joint examinations were within normal limits. During her hospital stay, she endorsed worsening shortness of breath and pedal oedema. She was diagnosed with new onset right ventricular failure and pulmonary hypertension.

Figure 1.

Bilateral finger contractures and dorsal skin thickening.

Figure 2.

Thenar atrophy of right hand.

Figure 3.

Prayer sign with inability to completely oppose palms and fingers.

Investigations

Laboratory studies were negative for rheumatoid factor, anticitrullinated protein and antineutrophil antibody. Thyroid function was stable and electrolytes were within normal range.

Haemoglobin A1c was 6.2%. Uric acid was 15.5 mg/dL. Hand X-rays revealed scattered interphalangeal joint space narrowing with small periarticular osteophytes and no erosive changes.

Echocardiogram was suggestive of infiltrative myocardial disease with mildly decreased left ventricular ejection fraction, severe left ventricular hypertrophy and moderate right ventricular hypokinesis (figures 4 and 5). Subsequent right heart catheterisation and biopsy was performed. The patient was found to have elevated left-sided filling pressures with wedge pressure of 25 mm Hg and moderate pulmonary hypertension with low cardiac index of 2.11 L/min/m². The endomyocardial biopsy revealed cardiac amyloidosis with positive congo red stain (figures 6 and 7). Further mass spectrometry analysis revealed aTTR amyloid with mutation Val122Ile.

Figure 4.

Transthoracic echocardiogram revealing infiltrative myocardial disease with severe left ventricular hypertrophy.

Figure 5.

Transthoracic echocardiogram revealing infiltrative myocardial disease with paradoxical septal motion.

Figure 6.

Endomyocardial biopsy, Congo red stain unpolarised, 100x. The interstitium has a salmon pink colour suggestive of amyloidosis.

Figure 7.

Endomyocardial biopsy, Congo red stain, polarised, 200x. Areas of blue-green colour are diagnostic of amyloidosis.

Differential diagnosis

The initial considerations on encountering a patient with bilateral hand pain and cramping included rheumatological, neurological, metabolic, endocrine and mechanical processes. Cramping pain could be provoked by trauma with acute or chronic sequalae of fracture, ligamentous or tendon injuries causing inflammation to the surrounding area, soft tissue swelling and decreased ability to perform hand grip. Cramping could also be caused by electrolyte abnormalities such as with potassium, magnesium, calcium and sodium dysregulation. In addition, endocrine abnormalities including hypothyroidism and acromegaly should be a part of the differential diagnosis. Burning sensation is worrisome for neurological abnormalities such as vitamin deficiencies or nerve impingement as in Carpal tunnel syndrome, which could result in thenar muscle atrophy. Evidence of swelling and synovitis, not seen in our patient, concern rheumatological disorders such as inflammatory arthritis (rheumatoid arthritis, seronegative arthritis, arthritis related to connective tissue disease) and crystal arthropathies (gout, pseudogout). Alternative rheumatological causes of decreased hand grip include myositis resulting in weakness (such as in inclusion body myositis which targets distal muscles) and scleroderma which results in sclerodactyly, to name a few.

Given that the patient had evidence of soft tissue swelling, she was treated with prednisone 30 mg for 5–7 days for presumed crystal arthropathy. Risk factors concerning gouty arthritis included chronic kidney disease, preceding osteoarthritis, use of diuretics and hyperuricaemia. Although the swelling mildly improved, the patient’s burning symptoms, level of stiffness and hand grip failed to improve. She was readmitted in September 2018 and November 2018 for heart failure exacerbations requiring variable diuretic use. She was again started on prednisone 2.5 mg daily and initiated on colchicine and allopurinol for suspected crystal arthropathy.

Because the symptoms persisted despite prednisone use, workup for alternative causes was started. Electrolytes and vitamin B12 were within normal range. Antinuclear antibodies and extractable nuclear antigens were negative in the evaluation of connective tissue disease. Rheumatoid factor and anticyclic citrullinated peptide were negative in the evaluation of rheumatoid arthritis. Given the failure of complete response to prednisone, the medication was stopped.

Electromyography and nerve conduction studies revealed very severe bilateral median nerve entrapments at the wrists with severe sensory and motor axon loss thought to be secondary to diabetic versus amyloid-related infiltrative disease. Anticonvulsant therapy (gabapentin) was given for trial of symptomatic relief and was mildly helpful. The differential diagnosis shifted to a multifactorial cause involving diabetic chieroarthropathy, progressive Carpal tunnel and amyloid arthropathy.

Treatment

The patient was treated for acute exacerbation of heart failure with varying doses of diuretics including furosemide 80 mg two times per day, metolazone and metoprolol. She was also started on amiodarone and warfarin for atrial fibrillation and dulaglutide and glipizide for diabetes mellitus type 2. Her cramping hand pain was treated symptomatically with gabapentin. Her diffuse hand cramping and stiffness persisted despite anticonvulsant therapy, diabetic control or the use of prednisone. Diclofenac gel provided mild-to-moderate relief from pain. Nonsteroidal anti-inflammataory drugs (NSAIDs) were not used secondary to chronic kidney disease. She was referred for occupational therapy.

Outcome and follow-up

The patient was readmitted in December 2018 with symptoms of diffuse swelling of extremities, dyspnoea on exertion, orthopnea and palpitations. She was treated for decompensated heart failure exacerbation and placed on furosemide drip for 1 week. Her stay was complicated by isolated drug-induced gout flare of her left knee with monosodium urate crystal positive synovial fluid analysis. Her knee pain resolved with intra-articular corticosteroid administration. She has since been followed up in the heart failure clinic as well as rheumatology clinic monthly. She continues to complain of diffuse hand cramping and stiffness, not associated with swelling, erythema or tenderness. She is awaiting approval for tafamadis, a novel medication to stabilise transthyretin and prevent dissociation and fibrillogenesis.⁵

Discussion

Amyloidosis is a systemic disease under the spectrum of proteopathies, characterised by abnormal protein structures driving the disease pathology.² Transthyretin (TTR) is a native tetramer protein of hepatic origin but, when mutated, dissociates into monomers which aggregate into amyloid fibrils.^{1 4} The tissue deposition of amyloid fibrils results in polyneuropathy, cardiomyopathy, hepatosplenomegaly, renomegaly, leptomeningeal, arthropathy and ocular disease.^{6 7}

There is a wide range of autosomal dominant mutations which are associated with TTR. The V30M mutation causes predominant polyneuropathy while V1221 causes severe cardiac involvement.^{3 8} Amyloid arthropathy represents about 5% of overall systemic disease burden. Rheumatological manifestations present as seronegative polyarthritis, Carpal tunnel syndrome and amyloid bone tumours.^9–11 TTR amyloid can deposit in osteoarthritic human cartilage and promote inflammation and catabolism. The synovial biopsy of involved joints shows abundance of macrophages. The paucity of plasma cells, explains the role of local innate immune cells in the progression of joint disease.¹² TTR can activate glycation end-product receptors and stimulate nuclear translocation of nuclear factor-κB, leading to cell death in cultured chondrocytes.^13–17

In amyloid arthropathy, the accumulation of amyloid fibrils leads to joint pains. The typical symptoms mimic those of rheumatoid arthritis given the symmetry and progression of symptoms over time.¹¹ However, the symptoms are thought to be a result of soft tissue swelling, rather than inflammation of the synovium.¹¹ This pathology leads to limitation of movement as seen in our patient. She lacked the diffuse tenderness and swelling in her hands that are commonly seen in other types of arthropathy, including but not limited to, crystal arthropathy (gout, pseudogout) and rheumatoid arthritis. Standard radiographs are often not helpful, as in our patient, although demineralisation, joint-space widening by amyloid infiltration and rarely, erosive disease can be seen.¹¹ Other contributors to joint pain in these patients include the development of median neuropathy progressing to Carpal tunnel syndrome, acute gout flares from diuretic use and kidney disease, worsening of diabetes mellitus from metabolic syndrome and propensity of osteoarthritis.

Controlling the underlying erratic immune proliferation prevents the progression of the arthropathy and sometimes may diminish existing arthritis. Symptomatic treatment is always a huge challenge. Though intra-articular steroid injections and radio synovectomy (intra-articular Yttrium-(29)) help with mono-oligoarthritis or oligoarthritis, in the majority of cases the polyarticular presentation warrants systemic treatment with oral steroids or NSAIDs.¹⁸

The initial manifestations of amyloid cardiac disease are conduction abnormalities, which occur much before any amyloid disease is evident on echocardiogram. In the later course of the cardiac disease, supraventricular arrhythmias tend to correlate with amyloid burden based on interventricular septal thickness and atrial dimensions.¹⁹ Our patient not only had diffuse ventricular hypokinesis, atrial dilation and intraventricular septum thickening, she also had paroxysmal atrial fibrillation. Management for patients who have familial amyloidotic polyneuropathy and cardiomyopathy involves assessing age, gender, echocardiogram and 24-hour Holter monitoring for conduction disturbances. Female patients were found to have a younger age of onset, which, including disease duration, all related to intraventricular septum thickness.¹⁹ Treatment of cardiomyopathies, valvopathies and conduction disturbances involves multidisciplinary groups between cardiology and cardiac subspecialties.

Mortality depends on the extent of cardiac involvement.^{18 20} Endomyocardial biopsy remains the standard diagnostic tool for amyloid cardiac disease, as the pathological analysis helps in the analysis of the type of amyloid protein. However, with advancement in technology, noninvasive techniques like echocardiogram with strain imaging and contraction fraction measurement can also differentiate between TTR and AL (IgM light chain) amyloid disease. Nuclear scintigraphy and cardiac MRI using extracellular volume measurement, late gadolinium enhancement and distinct T1 mapping also are effective diagnostic tests.²¹ In the USA, Val1221 mutation remains the most common mutation, with predominant cardiac involvement and is more severe in the older-adult male population.²²

The first line treatment of hereditary aTTR amyloidosis is liver transplantation; however follow-up studies show progressive disease even after liver transplant. This is likely as the non-mutant TTR (wild-type) protein is still being produced, contributing to worsening organ involvement. This is in accordance with the observation that the prognosis is better in patients who undergo early liver transplantation along with cardiac or other involved organ transplant.^23–25

Many clinical trials involving TTR tetramer stabilisers are in progress, among which tafamidis has proved to be beneficial in cardiomyopathy.⁵ Antisense oligonucleotides and small interfering RNAs mediating their activity by targeted cleavage of target mRNA are promising interventions under trial for the amelioration of TTR amyloidosis. These are available as parental nanoparticles in lipid formulation.^26–29 The role of these medications in amyloid arthropathy and associated musculoskeletal and peripheral neuropathic conditions is not yet known.

Learning points.

• The morbidity involved in systemic transthyretin amyloidosis varies from severe cardiac involvement to musculoskeletal and neuropathic involvement, limiting movement and activities of daily living.

• Because mutations are often seen later in life, small changes in the patient’s functional status could be a warning sign of systemic involvement of this disease process.

• In the evaluation of amyloid-related joint and soft tissue involvement, amyloid arthropathies, osteoarthritis, neuropathies and crystal arthropathies related to medication use can present concomitantly.

• Cardiovascular involvement is associated with high morbidity and mortality.