Unexplained dyspnea in a patient of chronic arsenicosis: A diagnostic challenge and learning curve for physicians.

Chronic arsenic exposure causes cutaneous effects like hyperkeratosis, peripheral vascular disease, hypertension, ischemic heart disease, non-cirrhotic portal hypertension, hepatomegaly, peripheral neuropathy, respiratory involvement, bad obstetrical outcome, hematological disturbances, and diabetes mellitus. Here we present a case of a 24-year-old lady, with chronic exposure to arsenic, presenting to us with progressive dyspnea. We found pulmonary arterial hypertension (PAH) as a cause of her dyspnea. PAH can occur in arsenicosis, secondary to arsenic-induced chronic obstructive pulmonary disease (COPD), lung fibrosis, and portal hypertension, which we excluded by appropriate investigations in our case. We also excluded a familial or heritable form of PAH. Thus, with the exclusion of all these secondary causes of PAH, as well as a hereditary cause, we came to a conclusion that this PAH might be due to chronic arsenic exposure. To the best of our knowledge, no case of PAH in chronic arsenicosis has been reported to date.

INTRODUCTION

Arsenic is an element that has raised concern from both the environmental and human health standpoints since the dawn of civilization. Chronic exposure, most commonly, is due to prolonged ingestion of water containing elevated levels of arsenic.[1] A report in 2001, has stated that around 150 million people are at risk from arsenic-contaminated ground water in the combined areas of West Bengal and its neighboring country, Bangladesh.[2] Dyspnea may occur in chronic arsenicosis due to heart failure, because of atherosclerotic hypertensive heart diseases, arsenic-induced restrictive pulmonary diseases, and portopulmonary hypertension.[3] In this case, we found isolated pulmonary arterial hypertension as the cause of dyspnea in a patient with chronic arsenicosis.

CASE REPORT

A 24-year-old, married girl, from the Nadia district of West Bengal, India, presented to us with progressive dyspnea for the last six months. She presented to us with dyspnea of Grade 4, as per the Modified Medical Research Council (MMRC) grading of dyspnea. She had cyanosis, resting oxygen saturation (SpO2) 81%, a pulse rate of 102/minute, blood pressure of 100/60 mmHg, and a respiratory rate of 26/minute. The internal jugular veins were engorged and pulsatile. Bilateral pitting pedal edema was present. On examination of her palm, hyperkeratosis and raindrop pigmentation was seen [Figure 1]. Examination of the respiratory system revealed no abnormality. On examination of her cardiovascular system, we found tachycardia and a loud pulmonary component of the second heart sound. Examination of her abdomen revealed a palpable tender liver. Thus, a clinical diagnosis of right heart failure was established. She was given oxygen at the rate of 6 liters/minute through a face mask. Her blood samples were sent for routine investigations. Her electrocardiogram revealed the presence of p-pulmonale. The routine blood investigation showed hemoglobin 9.1 g/dl, total leukocyte count 11,400/cubic millimeter, with neutrophil 80%, lymphocytes 17%, eosinophils 2%, and monocytes 1%; urea 23 mg/dl and creatinine 0.8 mg/dl; and sodium 133 mEq/L, potassium 3.7 mEq/L, and calcium 9.3 mg/dl. The liver function tests revealed no abnormality. Her enzyme-linked immunosorbent assay (ELISA) for human immunodeficiency virus (HIV) 1 and 2 antigen testing was negative. Her chest x-ray revealed no abnormality. Ultrasonography of the whole abdomen showed presence of mild hepatomegaly. Echocardiography revealed a grossly enlarged right ventricle and dilated right atrium, with intact an interatrial septum and interventricular septum and Grade 3 tricuspid regurgitation, with a measured mean pulmonary artery systolic pressure of 65 mmHg, which established the diagnosis of pulmonary arterial hypertension. We could not perform right heart catheterization due to lack of infrastructure. Transesophageal echocardiography (TEE) was also performed, but failed to reveal any intracardiac shunt [Figure 2]. Doppler-ultrasonography (Doppler-USG) of the abdomen revealed no evidence of portal hypertension. We sent her hair, nail, and drinking water from her residence to the School of Tropical Medicine in Kolkata for arsenic estimation and the report revealed 0.12 mg/L arsenic in the water sample (safe limit of arsenic content in drinking water is 0.05 mg/L in India and 0.01 mg/L, as per the World Health Organization statement), 2.66 μg/g in her hair, and 6.10 μg/g in her nail. High-resolution computed tomography (HRCT) scan of her thorax did not reveal any parenchymal abnormality. On computed tomography (CT)-angiography we found no embolus in the the pulmonary vasculature, but an enlarged main pulmonary artery trunk [Figure 3]. Subsequently, we planned to have investigations for connective tissue disorders (CTD), in order to detect the etiology of the pulmonary arterial hypertension (PAH). However, all our workups, including anti-centromere antibody, anti-ds DNA antibody, anti-Ro, anti-U3 and U1 RNP, and anti-phospholipid antibody were negative. After all these investigations we were in fact left with the idiopathic or heritable form of PAH. We then took her family history in detail, but failed to illicit any history suggestive of PAH in her family, even after repeated enquiry. Serum analysis for bone morphogenetic protein receptor 2 (BMPR-2) gene and activin receptor kinase-like 1 (ALK-1) gene failed to detect any mutation. We had virtually excluded almost all causes of PAH including familial causes. Thus, with the exclusion of all possible causes of PAH in the present case, we concluded that chronic arsenicosis may be responsible for PAH in this case.

Figure 1

Hyperkeratosis and raindrop pigmentation of the palm

Figure 2

Transesophageal echocardiography showing an enlarged right atrium and a right ventricle with intact interatrial septum and interventricular septum

Figure 3

CT angiography showing an enlarged main pulmonary artery

DISCUSSION

Arsenicosis is a multi-system disorder, with virtually no system exempted from its involvement. Cutaneous effects take the form of pigmentary changes, hyperkeratosis, and skin cancers. Peripheral vascular disease, hypertension, ischemic heart disease, non-cirrhotic portal hypertension, hepatomegaly, peripheral neuropathy, respiratory involvement, bad obstetrical outcome, hematological disturbances, and diabetes mellitus are among the other clinical features linked to arsenic toxicity. The proposed mechanism of arsenic-induced hypertension is accelerated atherosclerosis due to monoclonal expansion of smooth, production of reactive oxygen species, upregulation of inflammatory signals, and platelet aggregation.[456] Respiratory manifestations of arsenicosis include chronic obstructive pulmonary disease (COPD), bronchiectasis, and pulmonary fibrosis. Pulmonary arterial hypertension, as per literature, can occur in arsenicosis, secondary to COPD, lung fibrosis, and portal hypertension.

Pulmonary hypertension has been defined as an increase in mean pulmonary arterial pressure (PAP), ≥25 mmHg at rest, as assessed by right heart catheterization (RHC).[7] However, in our hospital there is no facility for RHC. We measured pulmonary artery systolic pressure by applying the formula (PA systolic pressure = tricuspid regurgitation pressure gradient + estimated right atrial pressure). Theoretically, the calculation of mean PAP from PA systolic pressure is possible (mean PAP = 0.61 × PA systolic pressure + 2 mmHg). Thus, we established the diagnosis of PAH in our patient. We excluded CTD by clinical examination and auto-antibody profile, left heart diseases by echocardiography, intra-cardiac shunt by TEE, portal hypertension by Doppler USG, pulmonary embolism by CT-angiography, as the probable causes of PAH. In our workups we got no evidence of portal hypertension, COPD or interstitial lung diseases causing PAH. We also excluded the possibility of heritable and familial PAH. In literature, we did not find any case of arsenic-induced isolated PAH. However, literature revealed many mechanisms causing endothelial dysfunction of systemic arteries like reactive oxygen species generation and inflammatory cascades mediated by cytokines in chronic arsenicosis patients.[6] On the basis of the above-mentioned mechanisms, we proposed that PAH in the present case might be due to chronic arsenic exposure and its toxicity. Careful attention to such cases in the future would provide more evidence of an association between the two conditions.