Year : 2017 | Volume
: 12 | Issue : 6 | Page : 185--188
Epidemic dropsy: A mimic of scleroderma?
Anupam Wakhlu, Rasmi Ranjan Sahoo
Department of Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
Department of Rheumatology, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Systemic sclerosis (SSc) is an autoimmune connective tissue disease involving the skin and internal organs and characterized pathologically by microvascular damage and increased deposition of connective tissue. Skin changes seen in SSc include edema, inflammation, induration, thickening, and progressive skin fibrosis. Histologically, skin fibrosis, accumulation of compact collagen in the dermis, effacement of rete pegs, infiltration by CD4+ T cells, and skin atrophy are observed. The “toxic oil syndrome” reported from Spain caused an outbreak of a scleroderma-like illness and was caused by ingestion of contaminated rapeseed cooking oil. Epidemic dropsy is caused by ingestion of mustard oil contaminated with the oil of Argemone mexicana. The major alkaloids in Argemone oil are sanguinarine and dihydrosanguinarine. These alkaloids produce widespread capillary dilatation, increased capillary permeability, and endothelial proliferation, akin to the toxic oil syndrome. Cutaneous manifestations include erythematous and tender bilaterally symmetrical pitting edema usually involving lower limbs, skin thickening and tethering, pigmentation, and presence of telangiectasias. The dermatopathology observed in epidemic dropsy includes atrophy and flattening of rete pegs, hypertrophy of and deposition of collagen, vascular dilatation and proliferation, and subcutaneous inflammation and fibrosis. Epidemic dropsy usually presents with subacute multisystem involvement, which may mimic a connective tissue disease. Skin involvement in epidemic dropsy may closely mimic cutaneous manifestations in SSc, both clinically and histologically. Thus, the clinician needs to be aware that epidemic dropsy with cutaneous involvement, especially if encountered sporadically, may be mistakenly diagnosed as scleroderma.
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Wakhlu A, Sahoo RR. Epidemic dropsy: A mimic of scleroderma?.Indian J Rheumatol 2017;12:185-188
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Wakhlu A, Sahoo RR. Epidemic dropsy: A mimic of scleroderma?. Indian J Rheumatol [serial online] 2017 [cited 2020 Jan 22 ];12:185-188
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Systemic sclerosis (SSc) is an autoimmune connective tissue disease involving the skin and internal organs and characterized pathologically by microvascular damage and excessive connective tissue deposition. Localized scleroderma, also known as linear scleroderma or morphea, remains confined to the skin and subcutaneous tissue, whereas systemic sclerosis (scleroderma), whether of the limited or diffuse cutaneous variety, involves internal organs as well. The major organ systems involved in SSc (other than cutaneous) include musculoskeletal, cardiac, pulmonary, gastrointestinal, renal, and vascular (characterized by the presence of Raynaud's phenomenon and digital ulcers).
Skin changes in SSc may occur in three stages. The initial stage is characterized by cutaneous edema and inflammation with puffiness of the hands and fingers. The sequel of this phase, which may last for many months, is induration and thickening of the skin. This longer phase of progressive skin fibrosis usually starts in acral distribution and causes diffuse skin involvement. The skin is thickened, tight, shiny, pigmented, and may be tethered as well. In the later stages of the disease, patients may develop areas of “vitiligo” like depigmentation, giving rise to the classical “salt and pepper” appearance of the skin. After 2–3 years of disease, some patients may develop a final stage of skin softening with normal looking skin. However, pigmentary changes, thinning of skin and tethering may remain to some extent. Other important cutaneous manifestations include digital pits and the development of telangiectasias.
Although the cause of SSc is not known, there is an interplay of genetic and environmental factors contributing to disease pathogenesis characterized by inflammatory, fibrotic, and vascular processes. Multiple environmental agents and drugs are implicated in causing scleroderma-like syndromes. Implicated chemicals include silica, heavy metals, benzene, vinyl chloride, toluene, and trichloroethylene. Implicated drugs include bleomycin, pentazocine, taxol, and cocaine. Nephrogenic fibrosing syndromes, caused by gadolinium-containing contrast material used in chronic renal failure, have recently been described, causing scleroderma-like skin induration. The “toxic oil syndrome” reported from Spain caused an outbreak of a scleroderma-like illness and was likely caused by ingestion of contaminated rapeseed cooking oil. Contamination of dietary supplements of L-tryptophan caused the epidemic of eosinophilia-myalgia syndrome in 1989. Both these syndromes caused an eosinophilic fasciitis (EF)-like disease with variable multisystem involvement.
Pathologically, SSc is characterized by the involvement of the microvasculature with obliteration and fibrosis involving multiple organs. Cutaneous and vascular inflammation is a consequence of infiltration by CD4+ lymphocytes. Skin fibrosis leads to expansion of the dermis with the destruction of hair follicles, sweat and sebaceous glands. Collagen accumulation occurs in the deep dermis and involves the fatty layer as well. Later on, the skin becomes atrophic with effacement of rete pegs and accumulation of compact collagen in the dermis. The scleroderma mimic EF is characterized by peripheral blood eosinophilia, normal epidermis, dermal and hypodermal sclerosis and thickening of the adipose lobular septa and perimysium.
Toxic Oil Syndrome
In 1981, thousands of people became ill near Madrid, Spain after ingestion of adulterated rapeseed cooking oil. Hundreds of people died as a consequence of the acute effects and well as the scleroderma-like illness that followed. The initial deaths reported were a consequence of chemical pneumonia with severe eosinophilia. Subsequent deaths were a consequence of severe persistent pulmonary hypertension and heart failure. A number of patients developed cutaneous findings mimicking SSc/EF as described above. The cardiotoxic component of rapeseed oil is erucic acid, which constitutes almost 40% of native rapeseed oil. The event central to the pathogenesis of this syndrome was the presence of severe vascular disease with endothelial injury and proliferation.
Epidemic dropsy is caused by ingestion of mustard oil (extracted from Brassica nigra) contaminated with the oil of Mexican/prickly poppy (Argemone mexicana). In vernacular Hindi language, Mexican poppy is known as “satyanashi,” which means annihilating or destructive. This name seems quite appropriate, given the severe deleterious effects of this oil. Mustard oil is used as a cooking medium in most parts of the Indian subcontinent. A. mexicana commonly grows alongside mustard plants and produces similar seeds. Inadvertent co-harvesting of seeds or adulteration leads to contamination of oil, resulting in epidemic dropsy., The first case of epidemic dropsy was reported from Calcutta, India in 1877 by Lyon. Since then, several outbreaks have been reported from India and elsewhere in the world from time to time. In an outbreak in India in 1999, around 3000 cases were reported from New Delhi with 60 deaths.
The major alkaloid content of Argemone oil is sanguinarine (5%) and dihydrosanguinarine (87%). The pathophysiology of epidemic dropsy is dominated by the adverse effects of these alkaloids, producing widespread capillary dilatation, increased capillary permeability, and endothelial proliferation, somewhat akin to the toxic oil syndrome. Loss of protein-rich plasma into the extravascular space activates the renin–angiotensin–aldosterone system with retention of fluid and sodium. A positive vicious cycle ensues, resulting in significant anasarca. The dependent edema does not respond well to diuretics and may take months to resolve. Similar pathophysiological changes occur in the heart, lungs, gut, and the kidneys. The predominant mechanisms of toxicity of alkaloids of A. mexicana are inhibition of Na +, K +-ATPase (especially intestinal and hepatic), destruction of cytochrome P-450, depletion of endogenous hepatic glutathione content, depletion of glycogen levels in the liver, free radical generation, and inhibition of the oxidation of pyruvate, lactate, and succinate.
The systemic pathological effects of the toxin may be seen in virtually any organ. The liver shows cytolysis and nuclear degeneration. Renal lesions include hemorrhages in glomeruli and interstitium with swelling of tubular epithelial cells. Gastric and duodenal erosions along with mucosal congestion may be seen. Thickening of interalveolar septa and congestion of lungs may occur. Heart may show degenerative changes with significant involvement of the coronary arteries. Eyes show venous dilation, tortuosity, hemorrhage, and edema of the disc. The nervous system is largely uninvolved, but there may be a prominent complaint of paresthesias in the affected limbs.
Any person consuming contaminated mustard oil may be affected. The disease usually occurs in epidemics, but sporadic cases are also seen. Epidemics are usually reported after the harvest of mustard crop. Subacute onset of diarrhoea and vomiting is present in majority of the patients. Other associated features may be moderate pyrexia, myalgia, arthralgia, and hair loss. Almost all patients have marked bilaterally symmetrical, tender pitting pedal edema, mostly involving the lower limbs but may involve the scrotum, abdominal wall, or present as anasarca. There is a significant blanchable cutaneous flush with or without the presence of telangiectasias, vascular nevi, and hyperpigmentation. Heart failure, pulmonary edema, pulmonary hypertension, chemical pneumonia, pericardial effusion, and renal involvement with attendant signs and symptoms may be seen. Eye involvement may be delayed but significant and may manifest as a diminution of vision, glaucoma, retinal hemorrhage, or vasculitis. Moderate-to-severe normocytic normochromic anemia is common. Sharma et al. reported pancytopenia in 54% of their cases.
The differential diagnosis of epidemic dropsy includes hypoproteinaemic states, beriberi, filariasis, severe hypothyroidism, and nephrotic syndrome. If skin is predominantly involved, then it may closely mimic scleroderma. Cutaneous involvement is discussed in detail below. Adulteration with argemone oil may be detected by the following tests: nitric acid test, ferric chloride test, cupric acetate test, and by paper chromatography.,
Cutaneous Involvement in Epidemic Dropsy
Chopra and Chaudhuri, De and Chatterjee gave detailed clinical and histopathological descriptions of cutaneous involvement in 1935.,, Increased vascularity of subcutaneous fat and marked dilatation of blood vessels of all layers of skin were characteristically present. Venules of subcutaneous fat were enlarged and dilated. The endothelial cells in these dilated vessels showed proliferation. Vascular nodules occurred in the skin due to new angiomatous growths and were called as “sarcoids.” The changes in the skin were described as:
Simple erythema with edema: Epidermis is normal; papillary and interpapillary edema of corium; dilatation of papillary, subpapillary, and subcutaneous blood vessels. Perivascular infiltration with endothelial cellsEarly stage of vascular sarcoid: Epidermis is normal; melanin deposits in the cells of rete pegs; papillary and interpapillary edema of corium; neovascularization; edematous collagen bundles; sweat and sebaceous glands normalNodule formation (sarcoid): Thinning of the horny layer and flattening of papillae; significant edema of papillary and subpapillary corium; collagen bundles look myxomatous/edematous; marked proliferation of endothelial cells; dilatation of capillaries in the subpapillary and cuticular plexus and perivascular infiltration; sweat and sebaceous glands absent in region of sarcoidFungating or ulcerative stage: Marked edema of prickle cell layer of epidermis with large vesicles separating the upper portion of rete from the horny layer; other places showed degenerative changes with infiltration of round cells and polymorphs leading to ulcerative changes in the epidermis; neovascularization with thrombi and hemorrhage; degeneration of rete pegs; collagen myxomatous; sarcoids can ulcerateHealing sarcoid stage: Only one or two layers of cells of rete pegs; superficial horny layer of epidermis shows thickening and detachment from subadjacent layer; papillae become flat with edema of the corium; vessels in the subpapillary zone are dilated; neovascularization.
More recently, Kar et al. described the histopathology of cutaneous involvement in epidemic dropsy. Acellular hyaline material was detected in the wall of dermal blood vessels. The superficial dermis was edematous, and the subcutis revealed central vessels with similar deposits. Many of the vessels revealed microthrombi. Sparse mononuclear infiltrate was also noted.
The authors share their experience of seven patients of epidemic dropsy with cutaneous manifestations mimicking SSc (unpublished data). All patients were taking newly harvested contaminated mustard oil. The duration of onset of symptoms varied from 5 to 25 days. All patients had skin involvement characterized by bilateral tender pitting pedal edema extending above the knees. There was erythema, warmth, and blanching of the skin on pressure. Edema of the abdominal wall and scrotum was seen in three patients. Papular skin lesions were seen in two patients. Skin thickening and tethering were seen in four patients, which became more prominent with time and as edema subsided. Telangiectasias and vascular ectasias were seen in two patients. All patients had cardiopulmonary signs and symptoms with heart failure. Diarrhea and vomiting were seen in three patients. All patients had moderate anemia, both normocytic normochromic and microcytic hypochromic. Cutaneous histology revealed epidermal flattening in four cases, inflammation extending into the subcutaneous fat in five cases, and subcutaneous fibrosis was present in six cases. Furthermore, an early inflammatory reaction around appendages with atrophy was observed. Vascular proliferation and dilatation, as well as perivascular inflammation, were present in all cases.
The dermatopathology observed in our cases and described elsewhere mimic the histological findings of scleroderma, with atrophy and flattening of rete pegs, hypertrophy of and deposition of collagen, vascular dilatation and proliferation, and subcutaneous inflammation and fibrosis.
Epidemic dropsy usually presents with subacute multisystem involvement, which may mimic a connective tissue disease. Cutaneous involvement in epidemic dropsy may closely mimic (clinically and histologically) skin involvement in SSc. The manifestations of epidemic dropsy closely mimic those of toxic oil syndrome, which is a known scleroderma mimic. Thus, mild-to-moderate epidemic dropsy with cutaneous involvement may be mistakenly diagnosed as scleroderma, and a clinician needs to aware of the same. The absence of Raynaud's phenomenon, classical sclerodactyly at the beginning, and absence of autoantibodies would be important differentiating features. The need for more studies which could evaluate the histological and cytokine profile in these patients, for example, transforming growth factor -beta, IL-17, Tumor necrosis factor-alpha, and vascular endothelial growth factor is limited by the paucity of cases owing to the epidemic nature of this disease.
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