Could a 3-year history of chronic diarrhea that has recently worsened to include nocturnal diarrhea and nasal regurgitation, along with decreased deep tendon reflexes, be related to an underlying condition such as amyloidosis, scleroderma, or autonomic neuropathy?

Systemic Amyloidosis with Autonomic and Gastrointestinal Involvement

Yes, these symptoms are highly likely related and strongly suggest systemic amyloidosis with autonomic neuropathy affecting both the peripheral nervous system and gastrointestinal tract. 1, 2

Why These Symptoms Point to a Unified Diagnosis

The combination of chronic diarrhea, nocturnal diarrhea, nasal regurgitation, and decreased deep tendon reflexes represents a classic constellation for systemic disease with autonomic dysfunction. 3, 1

Nocturnal diarrhea is an alarm feature that indicates organic pathology with high specificity, not a functional disorder. 3, 4 When combined with neurologic findings like decreased reflexes, this pattern demands evaluation for infiltrative or systemic diseases. 3

Amyloidosis as the Unifying Diagnosis

Amyloidosis causes peripheral neuropathy through amyloid protein deposition within nerves, leading to sensory, motor, and autonomic fiber dysfunction. 1

Autonomic neuropathy in amyloidosis affects multiple organ systems simultaneously:

• Gastrointestinal system: Chronic diarrhea occurs from autonomic dysfunction affecting gut motility and secretion 1, 2
• Peripheral nervous system: Decreased deep tendon reflexes result from sensorimotor polyneuropathy 1
• Esophageal dysfunction: Nasal regurgitation indicates esophageal dysmotility from autonomic involvement 1

The patient's 3-year history with recent worsening suggests progressive disease, which is characteristic of systemic amyloidosis. 4, 2

Critical Diagnostic Workup Required

Immediate Blood and Urine Tests

• Serum protein electrophoresis with immunofixation to detect monoclonal proteins 2
• Serum free light chain assay (kappa/lambda ratio) for primary amyloidosis 2
• Urine Bence Jones protein test to identify light chain excretion 2
• Complete blood count, comprehensive metabolic panel, and inflammatory markers (ESR, CRP) as these have high specificity for organic disease 3
• Anti-tissue transglutaminase IgA with total IgA to exclude celiac disease 5, 6
• Thyroid function tests to exclude hyperthyroidism 3, 4

Essential Tissue Diagnosis

Tissue biopsy with Congo red staining is mandatory for amyloidosis diagnosis. 2

• Rectal biopsy has high sensitivity (70-80%) and should be performed first as it is minimally invasive 2
• Sural nerve biopsy if rectal biopsy is negative but clinical suspicion remains high, particularly given the peripheral neuropathy 2
• Congo red staining showing apple-green birefringence under polarized light microscopy confirms amyloid deposition 2

Neurologic Evaluation

• Electromyography (EMG) and nerve conduction studies to characterize the neuropathy pattern 2
• Lumbar puncture with CSF analysis: Albuminocytologic dissociation (elevated protein with normal cell count) is characteristic of amyloid neuropathy 2
• The CSF protein can be markedly elevated (>1,000 mg/L) with normal cell counts 2

Bone Marrow Examination

• Bone marrow biopsy to identify abnormal plasma cells in primary (AL) amyloidosis 2
• Abnormal plasma cells typically comprise a small percentage but are diagnostic when present 2

Genetic Testing

• Transthyretin (TTR) gene sequencing to distinguish familial amyloid polyneuropathy from primary amyloidosis 2
• This is critical because treatment differs substantially between hereditary and acquired forms 1

Alternative Diagnoses to Consider

While amyloidosis is the leading diagnosis, systemic sclerosis (scleroderma) can also cause this symptom complex through autonomic dysfunction and gastrointestinal dysmotility. 3

Diabetes mellitus with advanced autonomic neuropathy should be evaluated, as it can cause chronic diarrhea, gastroparesis (leading to regurgitation), and decreased reflexes. 3 However, a 3-year progressive course without known diabetes makes this less likely.

Critical Pitfalls to Avoid

Do not diagnose irritable bowel syndrome or functional diarrhea in the presence of nocturnal diarrhea and neurologic findings. 6, 4 This combination mandates organic disease workup. 3

Do not attribute symptoms to separate unrelated conditions. The simultaneous presence of gastrointestinal and neurologic symptoms demands evaluation for systemic disease. 3, 1

Do not delay tissue biopsy if clinical suspicion is high. Amyloidosis has a poor prognosis and early diagnosis is essential for treatment. 2

Do not skip colonoscopy with biopsies. Even though amyloidosis is suspected, microscopic colitis and inflammatory bowel disease must be excluded, as they require histologic diagnosis and can coexist. 5, 6

Prognosis and Treatment Implications

Primary amyloidosis has a poor prognosis with multi-organ involvement. 2 Early diagnosis allows for chemotherapy targeting the abnormal plasma cell clone in AL amyloidosis or liver transplantation in hereditary TTR amyloidosis. 1

The presence of autonomic neuropathy as a presenting feature indicates significant disease burden and warrants urgent hematology/oncology referral once diagnosis is confirmed. 2