Introduction

Systemic AL amyloidosis is characterized by the production of abnormal immunoglobulin light chains by plasma cells. These proteins, known as amyloid, misfold and deposit in tissues, primarily affecting the heart, kidneys, liver, and peripheral nervous system. It is a rare disease with an incidence of approximately eight people per million per year, but its morbidity and mortality are high¹. The average age at diagnosis is 64 years, and 25% of patients die within the first six months². Diagnostic delays are common and have detrimental consequences for prognosis, making timely recognition of the disease critically important.

The clinical manifestations of AL amyloidosis are varied and can include chronic diarrhea, dermal and periorbital bruising (raccoon eyes), and hemolacria, a rare sign characterized by blood discharge through the lacrimal punctum. These symptoms are often nonspecific, contributing to diagnostic delays. Chronic diarrhea may result from amyloid infiltration in the gastrointestinal tract, while cutaneous manifestations and hemolacria result from vascular fragility induced by amyloid deposits³.

In the suspicion of systemic amyloidosis, one of the first-line detection tools for cardiac involvement is echocardiography. The most important predictive echocardiographic feature, though not specific, is left ventricular hypertrophy. Amyloid deposits produce a hyperreflective appearance that, in 2D images, gives a speckled appearance to the myocardium (granular sparkling texture).

The definitive diagnosis of AL amyloidosis and its classification are based on the histological demonstration of amyloid deposits and immunohistochemical typing. However, in the early stages, patients have scant amyloid deposits, significantly reducing the sensitivity of Congo red staining. Therefore, combining a skin fat biopsy with a rectal mucosa biopsy is recommended to increase diagnostic sensitivity; a negative result in both biopsies makes the diagnosis highly unlikely⁴.

The treatment goal is to achieve a complete hematological response to prevent the progression of organ damage. Therapeutic options include bone marrow transplantation and, for ineligible patients, chemotherapy consisting of dexamethasone, cyclophosphamide, bortezomib, and an anti-CD38 monoclonal antibody (daratumumab). These therapies have shown variable response and survival rates, underscoring the need for personalized treatment based on the individual characteristics of the patient and the stage of the disease⁵.

The following case report presents a patient with initial symptoms of chronic diarrhea accompanied by raccoon eyes and hemolacria, illustrating the diagnostic and therapeutic challenges of this disease.

Case Report

We present the case of a 63-year-old male patient, originally from Huaraz and residing in Lima, with a clinical history of hypertension for 30 years. The patient presented with a year-long history of watery bowel movements two to three times a day and a weight loss of 30 kg. He sought medical consultation with Gastroenterology, where endoscopy and colonoscopy studies were inconclusive. A week before his hospitalization, the patient experienced an increase in bowel movement frequency to three to four times a day, followed by an episode of syncope.

On physical examination, the patient was alert, lucid, and oriented. Bruising was observed in the anterior thoracic region approximately 3 x 3 cm, chest and lungs without alterations, regular cardiac rhythm with isolated extrasystoles, soft and depressible abdomen, non-tender, and mild to moderate edema in the lower limbs. Serum levels of hemoglobin, urea, creatinine, and glucose were within the reference range, while total proteins were decreased at 3.8 g/dL (range 6-8 g/dL). Urine examination showed severe proteinuria (+++/+++). The electrocardiogram revealed signs of left ventricular hypertrophy without ST segment changes. During his hospitalization, the patient presented with hemolacria and periorbital bruising (Figures 1 and 2).

Figure 1 Hemolacria in a patient with systemic AL amyloidosis 

Figura 2 Left eyelid ecchymosis in a patient with systemic AL amyloidosis. 

The coagulation profile showed a prolonged thromboplastin time of 60 seconds (range 25-35 seconds) with a deficiency of factor X. The 24-hour proteinuria was 900 mg/24 h. The urine electrophoretic proteinogram showed kappa/lambda light chains in a ratio of 0.81 (Table 1). Transthoracic echocardiography reported concentric hypertrophy of the left ventricle with a ground-glass appearance (Figure 3). Bone marrow biopsy showed 10% plasma cells. Given the probable case of systemic amyloidosis, biopsies of the colon, kidney, and subcutaneous connective tissue were performed; all were positive for Congo red staining, confirming the presence of amyloid deposits, with AL-type immunohistochemistry (Figure 4).

Figure 3 Transthoracic echocardiogram showing concentric hypertrophy of the left ventricle with a ground-glass appearance 

Figure 4.  Microscopic images of connective tissue with amyloid deposits in a patient with systemic AL amyloidosis. 

The diagnosis was conclusive for systemic AL amyloidosis with renal, cardiac, and gastrointestinal involvement. He received systemic chemotherapy with cyclophosphamide, dexamethasone, thalidomide, and bortezomib. After the first infusion of bortezomib, he developed atrial fibrillation and decompensated heart failure, leading to a change to an alternative regimen with lenalidomide, cyclophosphamide, and dexamethasone. Two months later, the patient passed away.

Discussion

Amyloidosis has 22 different types of localized forms and 18 types of systemic forms. The most common systemic forms are light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). Systemic AL amyloidosis, also known as primary or light-chain amyloidosis, is characterized by the production of abnormal immunoglobulin light chains by CD38+ plasma cells in the bone marrow. These proteins misfold and deposit in tissues as amyloid. It is a rare and complex disease associated with high morbidity and mortality. It affects approximately eight people per million, with a mean age at diagnosis of 64 years. Advanced age is the main risk factor, and 25% of patients with light-chain amyloidosis die within six months of diagnosis^6-9).

A review of the literature found no reported cases of hemolacria in patients with amyloidosis in Peru, Latin America, or worldwide. Only a few cases or images of hemolacria related to other pathologies have been found. Diagnostic delays are common and have detrimental consequences for patient prognosis. Therefore, clinical suspicion and the use of biomarkers and imaging technologies are vital for timely diagnosis. Systemic amyloidosis should be considered in the differential diagnosis of adult non-diabetic nephrotic syndrome. Additionally, the collapsing form is the most aggressive presentation of this type of glomerulopathy, and the severe form is associated with viral infectious processes such as HIV, CMV, and HBV, which were ruled out in this case.

Other clinical manifestations include heart failure with preserved ejection fraction, particularly if restrictive features are present; unexplained hepatomegaly without imaging abnormalities; peripheral neuropathy with distal sensory symptoms such as paresthesias and dysesthesias (though autonomic manifestations may occasionally be the presenting feature); and monoclonal gammopathy of undetermined significance with atypical clinical features⁷.. This list of clinical features should also include chronic diarrhea, cutaneous manifestations such as periorbital bruising (raccoon eyes), dermal bruising, macroglossia, and, as in our case, hemolacria.

This case report illustrates a case of systemic AL amyloidosis that began with chronic diarrhea. Despite repeated medical consultations and multiple endoscopic and colonoscopic studies, no timely diagnosis was made. Chronic diarrhea is one of the nonspecific and frequent symptoms of the disease, occurring in 40-60% of cases due to amyloid infiltration at the neuromuscular and mucosal levels of the gastrointestinal tract, often causing motility disturbances, resulting in diarrheal or subocclusive episodes. Hemorrhagic episodes due to mucosal infiltration and macroglossia occur in up to 50% of cases¹⁰.

During the course of hospitalization, ecchymotic dermal lesions were identified in the anterior thoracic and periorbital regions. Subsequently, the patient presented with bloody tears, a rare clinical sign known as hemolacria. This sign is produced by the accumulation of amyloid fibrils that increase vascular fragility. Additionally, factor X binds to amyloid fibrils, mainly in the liver and spleen, causing a deficiency of this factor. The most clinically significant coagulopathy in amyloidosis is factor X deficiency, the most frequent cause of bleeding. The incidence of acquired factor X deficiency associated with systemic AL amyloidosis ranges from 8.7% to 14%¹¹⁾⁽¹². There are no records of the incidence of hemolacria in patients with amyloidosis.

With clinical suspicion of systemic deposition disease, an echocardiogram was requested, revealing concentric left ventricular hypertrophy with a ground-glass appearance. Echocardiography is the cornerstone of non-invasive imaging for cardiac amyloidosis, as well as a first-line detection tool. The most important predictive echocardiographic feature, though not specific, is left ventricular hypertrophy, mainly in the interventricular septum. Amyloid deposits produce a hyperreflective appearance; 2D images give a speckled appearance to the myocardium (granular sparkling texture), most commonly in the ventricular septum or posterior wall, while the apex does not show this sign¹³.

Diagnosis and classification are based on the histological demonstration of amyloid deposits. Biopsies of affected organs, such as the kidney or heart, have high sensitivity; however, these invasive procedures can carry significant risks, such as bleeding and arrhythmia.

Abdominal subcutaneous fat, rectal, skin, salivary gland, and bone marrow biopsies are frequently used to detect amyloid deposits in patients with symptoms of the disease. However, the sensitivity values of these approaches vary considerably. Abdominal subcutaneous fat biopsy is a safe, simple, and low-cost method, with a sensitivity of 67% to 93%, but patients in the early stages of amyloidosis have scant amyloid deposits, significantly reducing the sensitivity of Congo red staining. Rectal biopsy has a sensitivity of 75% to 80%. Gertz et al.⁷reported that combining abdominal fat biopsy with bone marrow biopsy results in an 85% detection rate for diagnosis. Combining skin fat biopsy with rectal mucosa biopsy can identify amyloid deposits in nearly all patients, and a negative result from both biopsies makes the diagnosis highly unlikely¹⁴.

In this case, abdominal fat and rectal mucosa biopsies were performed, with Congo red staining yielding positive results, and immunohistochemistry, the current standard for determining the type of amyloid, typed it as AL.

The treatment goal for AL amyloidosis is to achieve a complete hematological response to halt the progression of organ damage. The first line of therapy is considered to be bone marrow transplantation. For ineligible patients, chemotherapy is proposed, consisting of dexamethasone, cyclophosphamide, bortezomib, and an anti-CD38 monoclonal antibody (daratumumab). This combination has shown a high complete hematological response rate and was approved by the Food and Drug Administration (FDA) in 2021. However, the limitation of this treatment in patients with advanced heart failure or renal damage should be considered¹⁵.