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Three-dimensional analysis of a calciphylaxis plaque: Clues to pathogenesis
Three-dimensional analysis of a calciphylaxis plaque: Clues to pathogenesis Sheila Au, MD,a and Richard I. Crawford, MDb Vancouver, British Columbia, Canada Background: Calciphylaxis is a rare, life-threatening disorder associated with chronic renal failure, presenting with ulcerating plaques leading to death by sepsis in 60% of patients. Calcification of subcutaneous arterioles, thromboses, and extravascular calcification have been demonstrated in incisional biopsy specimens. However, the sequence of these pathologic events is unknown. Objective: We examined a calciphylaxis plaque to document the wave of pathologic change from its center to its periphery. Methods: A calciphylaxis plaque was excised postmortem from a female patient. It was examined histologically along 12 radii from the center of the lesion to its periphery. Results: Calcification of small subcutaneous vessels was present in all histologically abnormal sections and extended further peripherally than extravascular calcification by up to 3.0 cm and further than subcutaneous thrombosis by up to 1.5 cm. Conclusion: Vascular mural calcification is an early and essential process in the development of a calciphylaxis plaque. (J Am Acad Dermatol 2002;47:53-7.)
C
alciphylaxis is a rare, life-threatening disorder that predominantly affects patients with end-stage renal disease. The typical affected patient is middle-aged, female, and obese, is undergoing dialysis, and may have significant metabolic derangements.1 A rapid onset of livedoid purpura and enlarging, tender, indurated subcutaneous plaques on the lower limbs or abdomen, frequently with evidence of acral vaso-occlusive disease, characterizes the condition.2 Cutaneous ischemia leads to skin necrosis, sepsis, and death in 60% of patients. Histologic examination of calciphylaxis lesions has repeatedly identified a characteristic triad: smallvessel mural calcification with or without endovascular fibrosis, extravascular calcification, and vascular thromboses. A histiocytic giant-cell reaction and From the Division of Dermatologya,b and Department of Pathology,b University of British Columbia, Vancouver. Funding sources: None. Conflict of interest: None. Portions of this work were presented at the 37th Annual Meeting of the American Society of Dermatopathology, Baltimore, Maryland, October 2000. Accepted for publication October 5, 2001. Reprint requests: Richard I. Crawford, MD, Laboratory, 2nd Floor Providence, St Paul’s Hospital, 1081 Burrard St, Vancouver, BC, Canada V6Z 1Y6. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 ⫹ 0 16/1/120927 doi:10.1067/mjd.2002.120927
variable inflammatory infiltrate may also be present. The sequence in which these events occur is still unclear and remains an area of controversy. There is a common, but not universal, association between calciphylaxis, hyperparathyroidism, and an elevated calcium:phosphate product, leading many to believe that vascular calcification is the initial pathogenic event. Findings of protein C and S deficiency in affected patients have led others to believe that a thrombotic diathesis is the primary event leading to tissue ischemia and necrosis. Clinically, calciphylaxis plaques begin as subcutaneous nodules and grow radially. We undertook to examine a calciphylaxis plaque in its entirety from center to periphery to document the wave of pathologic change within it. We hypothesized that vascular calcification would precede the other pathologic features, implicating it as an early pathogenic event in the onset of a calciphylaxis lesion.
METHODS A plaque of typical appearance, of recent onset, was excised postmortem from a 56-year-old woman with calciphylaxis. This patient had advanced diabetes, hypertension, obesity, end-stage renal failure, and secondary hyperparathyroidism. She presented with a 7-month history of a painful, crusted ulcer on the right calf, a 3-month history of bilateral, progressive, tender, firm, subcutaneous plaques on the anteromedial thighs, hips, and lower abdomen, and a 53
54 Au and Crawford
Fig 1. Crusted necrotic ulcer on calf and subcutaneous indurated plaque on thigh in patient with calciphylaxis.
J AM ACAD DERMATOL JULY 2002
Fig 3. Vertical section demonstrating grossly normal subcutaneous fat at periphery and hard, gray lesional subcutaneous fat centrally.
lar calcification, and vascular thromboses was recorded, as well as any other significant histologic findings. The maximum distance from the center of the plaque at which each abnormality was identified was documented. A topographic depiction of the pattern of pathologic change was created (Fig 4).
RESULTS
Fig 2. Retiform purpura overlying abdominal plaque of calciphylaxis.
2-week history of fixed, bluish discoloration of the fingers and toes (Figs 1 and 2). The clinical impression of calciphylaxis was supported by an incisional skin biopsy specimen that revealed subcutaneous vascular mural calcification, extravascular calcification, and thromboses within the dermis and subcutis. She underwent urgent parathyroidectomy in an attempt to attenuate the progression of her skin disease, but had cardiac arrest after the operation and died. On autopsy, we resected a calciphylaxis plaque from her pannus with a rim of grossly normal skin and subcutaneous tissue. The subcutaneous fat was noted to be hard and gray within the affected area (Fig 3). The center of the lesion was defined and marked with a felt-tipped marker, and 12 radii, 30° apart, were drawn from the center of the lesion to its periphery. The plaque was examined histologically along these radii using hematoxylin-eosin, von Kossa, and Martius scarlet blue stains. The presence or absence of vascular mural calcification, extravascu-
Most of the pathologic change was confined to the subcutaneous tissue. Three major histologic changes were encountered. Vascular mural calcification was seen extensively within the walls of small subcutaneous arteries and arterioles (Fig 5). Vascular thromboses were seen in many dermal and subcutaneous blood vessels (Fig 6). Extravascular calcification was present between and within lipocytes (Fig 5). Vascular calcification was the most common finding, present in all histologically abnormal sections. Although closely followed by the other abnormalities, this calcification extended further peripherally than extravascular calcification by up to 3 cm and further peripherally than subcutaneous thrombosis by up to 1.5 cm (Fig 4). The skin and subcutaneous fat distal to the peripheral boundary of vascular calcification were normal. In many areas, the pathologic changes extended past the clinical boundary of the calciphylaxis plaque into areas of grossly normal skin, and in some areas extended to the edge of the resected tissue.
DISCUSSION The true pathogenesis, most appropriate treatment, and even correct nomenclature for this disorder have always been a subject of debate. In 1962 Hans Selye3 coined the term calciphylaxis after observing soft-tissue calcification in an animal model. He succeeded in inducing soft-tissue calcium deposition by rendering rats hypercalcemic with vitamin
Au and Crawford 55
J AM ACAD DERMATOL VOLUME 47, NUMBER 1
Fig 4. Topographic depiction of calciphylaxis plaque.
Fig 5. Vascular mural calcification and extravascular calcification between lipocytes. (Hematoxylin-eosin stain; original magnification ⫻800.)
Fig 6. Thrombosis of small subcutaneous blood vessels. (Hematoxylin-eosin stain; original magnification ⫻250.)
D or parathyroid hormone injections and then challenging the rats with various physical and chemical agents. He likened this process to “anaphylaxis,” where vitamin D and parathyroid hormone were “sensitizers,” and subsequent insults were “challengers.” Selye3 observed calcification and tissue necrosis in many tissues, but the specific pattern of vascular calcification seen in humans with calciphylaxis was not observed.4 Some currently subscribe to the notion that calciphylaxis as we know it today is not the same disease described by Selye 40 years ago.1 Others continue to apply Selye’s rat model to the human disorder, where end-stage renal disease, secondary hyperparathyroidism, and a high calcium: phosphate product are the “sensitizers” and corticosteroids, iron injections, or blood product transfusions are the “challenging agents” that precipitate calcium deposition.5
The histopathologic findings in calciphylaxis have been extensively reported. Most reports document findings present in punch biopsy, incisional biopsy, and surgical specimens. To our knowledge, intact plaques have not been examined in the manner we have described herein. A universal finding in all such biopsy specimens is the presence of intravascular calcium deposition within the media of dermal and subcutaneous arterioles,6,7 often accompanied by endovascular fibrosis. Also observed are intravascular thrombi and extravascular calcification,1,2,8 but these are seen to a lesser degree than medial calcinosis.7 It is the constant presence of vascular calcification that has led many to believe that this is the primary pathogenic process in calciphylaxis. Some have even urged that the disease be more appropriately renamed “uremic small-artery disease with medial calcification and intimal hyper-
56 Au and Crawford
plasia,”2 “calcific uremic arteriolopathy,”9 or “vascular calcification-cutaneous necrosis syndrome.”10 Despite these findings, other hypotheses regarding the primary cause of cutaneous ischemia in calciphylaxis exist. Recent reports have implicated thrombotic diatheses such as protein C and S deficiency in causing vascular thromboses observed in calciphylaxis.8,11-13 Proponents of this theory suggest that vascular calcification in and of itself is very common in patients with renal failure, whereas calciphylaxis is rare, suggesting an alternate pathogenic mechanism. They believe that a hypercoagulable state may lead to thrombosis in the presence of this pre-existing vascular damage, resulting in clinical calciphylaxis. It is well known that patients on dialysis can experience functional protein C and S deficiencies, but patients with calciphylaxis reportedly have lower levels.11 These proteins are integral to anticoagulation. Protein C is activated on the endothelial surface, and with protein S as its cofactor, cleaves factors 5a and 8, inhibiting coagulation.11 Deficits in either protein may lead to thromboses. Coumarin necrosis, caused by acute low plasma protein C levels, can resemble calciphylaxis clinically. Case reports have documented patients with measured thrombotic diatheses and calciphylaxis, but a clear association has yet to be substantiated. Thrombosis as a primary etiology is also disfavored, because thrombi are not found in the majority of biopsy specimens of calciphylaxis,6 and because reductions in protein C and S levels may occur as a secondary phenomenon in hypercoagulable states. It is possible, however, that in vessels already narrowed by calcification, a hypercoagulable state may predispose to thromboses.14,15 It is also unlikely that the small-vessel calcification seen can be attributed to uremia alone. Although a large proportion of uremic patients already have progressive medial calcinosis,7 it usually affects large- and medium-sized vessels and does not usually cause ischemia of proximal tissues,16 in contrast to the rapid onset of smallvessel occlusive disease observed in calciphylaxis.2 The distribution of arteriolar involvement in calciphylaxis has been demonstrated to correspond to areas of skin necrosis, and clinically normal skin in uremic patients has not demonstrated vascular calcification.17 This again lends credence to the concept that small-vessel calcification represents a primary pathogenic process in calciphylaxis rather than an underlying baseline state. Our case study indicates that medial vessel calcification is the first histopathologically detectable event in the evolution of a calciphylaxis plaque. This is based on the assumption that calciphylaxis plaques expand radially from a central apex. In our
J AM ACAD DERMATOL JULY 2002
opinion, microscopic changes seen peripherally represent the earliest pathology at the leading edge of a lesion, whereas central abnormalities reflect older and better-developed pathology. Medial vessel calcification was a universal finding in all histologically abnormal tissue, and was seen in the absence of any other abnormality at the periphery of the plaque in several places. Thrombosis and extravascular calcification lagged behind in certain areas. In no section were either of these changes present in the absence of vascular calcification. The mechanism of calciphylaxis is unknown. It is well established that uremic patients have derangements in calcium and phosphate homeostasis.2 Lack of functional vitamin D in chronic renal failure results in decreased intestinal calcium absorption. This leads to hypocalcemia and compensatory secondary hyperparathyroidism in an attempt to normalize the serum calcium. Concomitant phosphate retention leads to hyperphosphatemia and an elevated calcium:phosphate product. Although most patients with calciphylaxis demonstrate hyperparathyroidism and elevated calcium:phosphate product, this is by no means universal.18 In fact, no single metabolic profile can be uniformly identified in patients with this enigmatic disease. Calciphylaxis has been reported in patients without renal failure, secondary hyperparathyroidism, or abnormal calcium:phosphate ratio, making it difficult to implicate one particular cause.7 Calciphylaxis is clearly a complex disorder, and a multifactorial etiology is likely. Risk factors may include uremia, secondary hyperparathyroidism, altered calcium:phosphate ratio, pre-existing peripheral vascular disease, diabetes, and obesity.1 A mathematical formula has actually been proposed to identify which patients with end-stage renal disease are at risk for calciphylaxis, using serum calcium, phosphorus, alkaline phosphatase, and parathyroid hormone levels.19 A formulaic product greater than 1000 units portends a higher risk of calciphylaxis; however, this conclusion is based on results from a small number of patients. Why the tunica media of small arteries and arterioles is the primary site of calcification remains purely speculative. It is recognized that the tunica media is especially predisposed to calcification,20 but the chemical composition of these calcifications has not been elucidated.7 The tunica media is the smooth muscle layer of the vessel wall. It is possible that patients with calciphylaxis have previously existing microvascular disease from diabetes or atherosclerosis, causing damage to smooth muscle cells. Degenerating smooth muscle cells may then bind calcium in the presence of an abnormal metabolic milieu. In another calcification disorder, metastatic
J AM ACAD DERMATOL VOLUME 47, NUMBER 1
calcification, tissue pH is thought to be important in deposition of calcium salts.7 These salts are deposited in alkaline tissues such as the kidney and gastric mucosa, presumably because the solubility of phosphate and calcium salts is lower in a high pH environment. The microenvironment around the tunica media may similarly facilitate precipitation of calcium salts. Trauma may also be involved in inducing dystrophic smooth muscle calcification.1 The lesions of calciphylaxis tend to occur in areas of high adiposity, where an expanded panniculus may subject blood vessels to increased tensile stress as they course through the fibroelastic septae anchoring fat to dermis. Microorganisms act as a nidus for calcium salt deposition in vitro and are considered to be potential pathogenic factors.21 It is likely that all 3 major histologic changes seen in calciphylaxis reflect pathogenic processes that act in concert to create the ultimate clinical picture. However, identifying the primary event may be of value in directing ultimate patient management. This case study supports the hypothesis that calciphylaxis is a disorder of subcutaneous arteriolar calcification. Medial-vessel calcification was found to be at the leading edge of an expanding lesion. This was followed by thrombosis, possibly resulting from vascular damage, sluggish blood flow, or a hypercoagulable state, and a calcifying panniculitis, another reflection of deranged calcium homeostasis. Further study into the biochemical mechanisms behind this calcium deposition should lead to a better understanding of this devastating condition and to more effective prevention and treatment. REFERENCES 1. Janigan DT, Hirsch DJ, Klassen GA, MacDonald AS. Calcified subcutaneous arterioles with infarcts of the subcutis and skin (“calciphylaxis”) in chronic renal failure. Am J Kidney Dis 2000;35: 588-97. 2. Hafner J, Keusch G, Wahl C, Sauter B, Hurlimann A, von Weizsacker F, et al. Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy [see comments]. J Am Acad Dermatol 1995; 33:954-62. 3. Selye H. Calciphylaxis. Chicago: University of Chicago Press; 1962.
Au and Crawford 57
4. Ivker RA, Woosley J, Briggaman RA. Calciphylaxis in three patients with end-stage renal disease. Arch Dermatol 1995;131:63-8. 5. Worth RL. Calciphylaxis: pathogenesis and therapy. J Cutan Med Surg 1998;2:245-8. 6. Essary LR, Wick MR. Cutaneous calciphylaxis: an underrecognized clinicopathologic entity. Am J Clin Pathol 2000;113:280-7. 7. Fischer AH, Morris DJ. Pathogenesis of calciphylaxis: study of three cases with literature review. Hum Pathol 1995;26:1055-64. 8. Rostaing L, el Feki S, Delisle MB, Durand-Malgouyres C, Ton-That H, Bonafe JL, et al. Calciphylaxis in a chronic hemodialysis patient with protein S deficiency. Am J Nephrol 1995;15:524-7. 9. Coates T, Kirkland GS, Dymock RB, Murphy BF, Brealey JK, Mathew TH, et al. Cutaneous necrosis from calcific uremic arteriolopathy [see comments]. Am J Kidney Dis 1998;32:384-91. 10. Lipsker D, Chosidow O, Martinez F, Challier E, Frances C. Lowcalcium dialysis in calciphylaxis [letter]. Arch Dermatol 1997;133:798-9. 11. Mehta RL, Scott G, Sloand JA, Francis CW. Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis. Am J Med 1990;88:252-7. 12. Perez-Mijares R, Guzman-Zamudio JL, Payan-Lopez J, Rodriguez-Fernandez A, Gomez-Fernandez P, Almaraz-Jimenez M. Calciphylaxis in a haemodialysis patient: functional protein S deficiency? Nephrol Dial Transplant 1996;11:1856-9. 13. Kant KS, Glueck HI, Coots MC, Tonne VA, Brubaker R, Penn I. Protein S deficiency and skin necrosis associated with continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1992;19: 264-71. 14. Whittam LR, McGibbon DH, MacDonald DM. Proximal cutaneous necrosis in association with chronic renal failure. Br J Dermatol 1996;135:778-81. 15. Kalaaji AN, Douglass MC, Chaffins M, Lowe L. Calciphylaxis: a cause of necrotic ulcers in renal failure. J Cutan Med Surg 1998; 2:242-4. 16. MacLean C, Brahn E. Systemic lupus erythematosus: calciphylaxis induced cardiomyopathy [see comments]. J Rheumatol 1995;22:177-9. 17. Chan YL, Mahony JF, Turner JJ, Posen S. The vascular lesions associated with skin necrosis in renal disease. Br J Dermatol 1983;109:85-95. 18. Smiley CM, Hanlon SU, Michel DM. Calciphylaxis in moderate renal insufficiency: changing disease concepts. Am J Nephrol 2000;20:324-8. 19. Levin A, Mehta RL, Goldstein MB. Mathematical formulation to help identify the patient at risk of ischemic tissue necrosis—a potentially lethal complication of chronic renal failure. Am J Nephrol 1993;13:448-53. 20. Gilson RT, Milum E. Calciphylaxis: case report and treatment review. Cutis 1999;63:149-53. 21. Oh DH, Eulau D, Tokugawa DA, McGuire JS, Kohler S. Five cases of calciphylaxis and a review of the literature [see comments]. J Am Acad Dermatol 1999;40:979-87.
C
alciphylaxis is a rare, life-threatening disorder that predominantly affects patients with end-stage renal disease. The typical affected patient is middle-aged, female, and obese, is undergoing dialysis, and may have significant metabolic derangements.1 A rapid onset of livedoid purpura and enlarging, tender, indurated subcutaneous plaques on the lower limbs or abdomen, frequently with evidence of acral vaso-occlusive disease, characterizes the condition.2 Cutaneous ischemia leads to skin necrosis, sepsis, and death in 60% of patients. Histologic examination of calciphylaxis lesions has repeatedly identified a characteristic triad: smallvessel mural calcification with or without endovascular fibrosis, extravascular calcification, and vascular thromboses. A histiocytic giant-cell reaction and From the Division of Dermatologya,b and Department of Pathology,b University of British Columbia, Vancouver. Funding sources: None. Conflict of interest: None. Portions of this work were presented at the 37th Annual Meeting of the American Society of Dermatopathology, Baltimore, Maryland, October 2000. Accepted for publication October 5, 2001. Reprint requests: Richard I. Crawford, MD, Laboratory, 2nd Floor Providence, St Paul’s Hospital, 1081 Burrard St, Vancouver, BC, Canada V6Z 1Y6. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 ⫹ 0 16/1/120927 doi:10.1067/mjd.2002.120927
variable inflammatory infiltrate may also be present. The sequence in which these events occur is still unclear and remains an area of controversy. There is a common, but not universal, association between calciphylaxis, hyperparathyroidism, and an elevated calcium:phosphate product, leading many to believe that vascular calcification is the initial pathogenic event. Findings of protein C and S deficiency in affected patients have led others to believe that a thrombotic diathesis is the primary event leading to tissue ischemia and necrosis. Clinically, calciphylaxis plaques begin as subcutaneous nodules and grow radially. We undertook to examine a calciphylaxis plaque in its entirety from center to periphery to document the wave of pathologic change within it. We hypothesized that vascular calcification would precede the other pathologic features, implicating it as an early pathogenic event in the onset of a calciphylaxis lesion.
METHODS A plaque of typical appearance, of recent onset, was excised postmortem from a 56-year-old woman with calciphylaxis. This patient had advanced diabetes, hypertension, obesity, end-stage renal failure, and secondary hyperparathyroidism. She presented with a 7-month history of a painful, crusted ulcer on the right calf, a 3-month history of bilateral, progressive, tender, firm, subcutaneous plaques on the anteromedial thighs, hips, and lower abdomen, and a 53
54 Au and Crawford
Fig 1. Crusted necrotic ulcer on calf and subcutaneous indurated plaque on thigh in patient with calciphylaxis.
J AM ACAD DERMATOL JULY 2002
Fig 3. Vertical section demonstrating grossly normal subcutaneous fat at periphery and hard, gray lesional subcutaneous fat centrally.
lar calcification, and vascular thromboses was recorded, as well as any other significant histologic findings. The maximum distance from the center of the plaque at which each abnormality was identified was documented. A topographic depiction of the pattern of pathologic change was created (Fig 4).
RESULTS
Fig 2. Retiform purpura overlying abdominal plaque of calciphylaxis.
2-week history of fixed, bluish discoloration of the fingers and toes (Figs 1 and 2). The clinical impression of calciphylaxis was supported by an incisional skin biopsy specimen that revealed subcutaneous vascular mural calcification, extravascular calcification, and thromboses within the dermis and subcutis. She underwent urgent parathyroidectomy in an attempt to attenuate the progression of her skin disease, but had cardiac arrest after the operation and died. On autopsy, we resected a calciphylaxis plaque from her pannus with a rim of grossly normal skin and subcutaneous tissue. The subcutaneous fat was noted to be hard and gray within the affected area (Fig 3). The center of the lesion was defined and marked with a felt-tipped marker, and 12 radii, 30° apart, were drawn from the center of the lesion to its periphery. The plaque was examined histologically along these radii using hematoxylin-eosin, von Kossa, and Martius scarlet blue stains. The presence or absence of vascular mural calcification, extravascu-
Most of the pathologic change was confined to the subcutaneous tissue. Three major histologic changes were encountered. Vascular mural calcification was seen extensively within the walls of small subcutaneous arteries and arterioles (Fig 5). Vascular thromboses were seen in many dermal and subcutaneous blood vessels (Fig 6). Extravascular calcification was present between and within lipocytes (Fig 5). Vascular calcification was the most common finding, present in all histologically abnormal sections. Although closely followed by the other abnormalities, this calcification extended further peripherally than extravascular calcification by up to 3 cm and further peripherally than subcutaneous thrombosis by up to 1.5 cm (Fig 4). The skin and subcutaneous fat distal to the peripheral boundary of vascular calcification were normal. In many areas, the pathologic changes extended past the clinical boundary of the calciphylaxis plaque into areas of grossly normal skin, and in some areas extended to the edge of the resected tissue.
DISCUSSION The true pathogenesis, most appropriate treatment, and even correct nomenclature for this disorder have always been a subject of debate. In 1962 Hans Selye3 coined the term calciphylaxis after observing soft-tissue calcification in an animal model. He succeeded in inducing soft-tissue calcium deposition by rendering rats hypercalcemic with vitamin
Au and Crawford 55
J AM ACAD DERMATOL VOLUME 47, NUMBER 1
Fig 4. Topographic depiction of calciphylaxis plaque.
Fig 5. Vascular mural calcification and extravascular calcification between lipocytes. (Hematoxylin-eosin stain; original magnification ⫻800.)
Fig 6. Thrombosis of small subcutaneous blood vessels. (Hematoxylin-eosin stain; original magnification ⫻250.)
D or parathyroid hormone injections and then challenging the rats with various physical and chemical agents. He likened this process to “anaphylaxis,” where vitamin D and parathyroid hormone were “sensitizers,” and subsequent insults were “challengers.” Selye3 observed calcification and tissue necrosis in many tissues, but the specific pattern of vascular calcification seen in humans with calciphylaxis was not observed.4 Some currently subscribe to the notion that calciphylaxis as we know it today is not the same disease described by Selye 40 years ago.1 Others continue to apply Selye’s rat model to the human disorder, where end-stage renal disease, secondary hyperparathyroidism, and a high calcium: phosphate product are the “sensitizers” and corticosteroids, iron injections, or blood product transfusions are the “challenging agents” that precipitate calcium deposition.5
The histopathologic findings in calciphylaxis have been extensively reported. Most reports document findings present in punch biopsy, incisional biopsy, and surgical specimens. To our knowledge, intact plaques have not been examined in the manner we have described herein. A universal finding in all such biopsy specimens is the presence of intravascular calcium deposition within the media of dermal and subcutaneous arterioles,6,7 often accompanied by endovascular fibrosis. Also observed are intravascular thrombi and extravascular calcification,1,2,8 but these are seen to a lesser degree than medial calcinosis.7 It is the constant presence of vascular calcification that has led many to believe that this is the primary pathogenic process in calciphylaxis. Some have even urged that the disease be more appropriately renamed “uremic small-artery disease with medial calcification and intimal hyper-
56 Au and Crawford
plasia,”2 “calcific uremic arteriolopathy,”9 or “vascular calcification-cutaneous necrosis syndrome.”10 Despite these findings, other hypotheses regarding the primary cause of cutaneous ischemia in calciphylaxis exist. Recent reports have implicated thrombotic diatheses such as protein C and S deficiency in causing vascular thromboses observed in calciphylaxis.8,11-13 Proponents of this theory suggest that vascular calcification in and of itself is very common in patients with renal failure, whereas calciphylaxis is rare, suggesting an alternate pathogenic mechanism. They believe that a hypercoagulable state may lead to thrombosis in the presence of this pre-existing vascular damage, resulting in clinical calciphylaxis. It is well known that patients on dialysis can experience functional protein C and S deficiencies, but patients with calciphylaxis reportedly have lower levels.11 These proteins are integral to anticoagulation. Protein C is activated on the endothelial surface, and with protein S as its cofactor, cleaves factors 5a and 8, inhibiting coagulation.11 Deficits in either protein may lead to thromboses. Coumarin necrosis, caused by acute low plasma protein C levels, can resemble calciphylaxis clinically. Case reports have documented patients with measured thrombotic diatheses and calciphylaxis, but a clear association has yet to be substantiated. Thrombosis as a primary etiology is also disfavored, because thrombi are not found in the majority of biopsy specimens of calciphylaxis,6 and because reductions in protein C and S levels may occur as a secondary phenomenon in hypercoagulable states. It is possible, however, that in vessels already narrowed by calcification, a hypercoagulable state may predispose to thromboses.14,15 It is also unlikely that the small-vessel calcification seen can be attributed to uremia alone. Although a large proportion of uremic patients already have progressive medial calcinosis,7 it usually affects large- and medium-sized vessels and does not usually cause ischemia of proximal tissues,16 in contrast to the rapid onset of smallvessel occlusive disease observed in calciphylaxis.2 The distribution of arteriolar involvement in calciphylaxis has been demonstrated to correspond to areas of skin necrosis, and clinically normal skin in uremic patients has not demonstrated vascular calcification.17 This again lends credence to the concept that small-vessel calcification represents a primary pathogenic process in calciphylaxis rather than an underlying baseline state. Our case study indicates that medial vessel calcification is the first histopathologically detectable event in the evolution of a calciphylaxis plaque. This is based on the assumption that calciphylaxis plaques expand radially from a central apex. In our
J AM ACAD DERMATOL JULY 2002
opinion, microscopic changes seen peripherally represent the earliest pathology at the leading edge of a lesion, whereas central abnormalities reflect older and better-developed pathology. Medial vessel calcification was a universal finding in all histologically abnormal tissue, and was seen in the absence of any other abnormality at the periphery of the plaque in several places. Thrombosis and extravascular calcification lagged behind in certain areas. In no section were either of these changes present in the absence of vascular calcification. The mechanism of calciphylaxis is unknown. It is well established that uremic patients have derangements in calcium and phosphate homeostasis.2 Lack of functional vitamin D in chronic renal failure results in decreased intestinal calcium absorption. This leads to hypocalcemia and compensatory secondary hyperparathyroidism in an attempt to normalize the serum calcium. Concomitant phosphate retention leads to hyperphosphatemia and an elevated calcium:phosphate product. Although most patients with calciphylaxis demonstrate hyperparathyroidism and elevated calcium:phosphate product, this is by no means universal.18 In fact, no single metabolic profile can be uniformly identified in patients with this enigmatic disease. Calciphylaxis has been reported in patients without renal failure, secondary hyperparathyroidism, or abnormal calcium:phosphate ratio, making it difficult to implicate one particular cause.7 Calciphylaxis is clearly a complex disorder, and a multifactorial etiology is likely. Risk factors may include uremia, secondary hyperparathyroidism, altered calcium:phosphate ratio, pre-existing peripheral vascular disease, diabetes, and obesity.1 A mathematical formula has actually been proposed to identify which patients with end-stage renal disease are at risk for calciphylaxis, using serum calcium, phosphorus, alkaline phosphatase, and parathyroid hormone levels.19 A formulaic product greater than 1000 units portends a higher risk of calciphylaxis; however, this conclusion is based on results from a small number of patients. Why the tunica media of small arteries and arterioles is the primary site of calcification remains purely speculative. It is recognized that the tunica media is especially predisposed to calcification,20 but the chemical composition of these calcifications has not been elucidated.7 The tunica media is the smooth muscle layer of the vessel wall. It is possible that patients with calciphylaxis have previously existing microvascular disease from diabetes or atherosclerosis, causing damage to smooth muscle cells. Degenerating smooth muscle cells may then bind calcium in the presence of an abnormal metabolic milieu. In another calcification disorder, metastatic
J AM ACAD DERMATOL VOLUME 47, NUMBER 1
calcification, tissue pH is thought to be important in deposition of calcium salts.7 These salts are deposited in alkaline tissues such as the kidney and gastric mucosa, presumably because the solubility of phosphate and calcium salts is lower in a high pH environment. The microenvironment around the tunica media may similarly facilitate precipitation of calcium salts. Trauma may also be involved in inducing dystrophic smooth muscle calcification.1 The lesions of calciphylaxis tend to occur in areas of high adiposity, where an expanded panniculus may subject blood vessels to increased tensile stress as they course through the fibroelastic septae anchoring fat to dermis. Microorganisms act as a nidus for calcium salt deposition in vitro and are considered to be potential pathogenic factors.21 It is likely that all 3 major histologic changes seen in calciphylaxis reflect pathogenic processes that act in concert to create the ultimate clinical picture. However, identifying the primary event may be of value in directing ultimate patient management. This case study supports the hypothesis that calciphylaxis is a disorder of subcutaneous arteriolar calcification. Medial-vessel calcification was found to be at the leading edge of an expanding lesion. This was followed by thrombosis, possibly resulting from vascular damage, sluggish blood flow, or a hypercoagulable state, and a calcifying panniculitis, another reflection of deranged calcium homeostasis. Further study into the biochemical mechanisms behind this calcium deposition should lead to a better understanding of this devastating condition and to more effective prevention and treatment. REFERENCES 1. Janigan DT, Hirsch DJ, Klassen GA, MacDonald AS. Calcified subcutaneous arterioles with infarcts of the subcutis and skin (“calciphylaxis”) in chronic renal failure. Am J Kidney Dis 2000;35: 588-97. 2. Hafner J, Keusch G, Wahl C, Sauter B, Hurlimann A, von Weizsacker F, et al. Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy [see comments]. J Am Acad Dermatol 1995; 33:954-62. 3. Selye H. Calciphylaxis. Chicago: University of Chicago Press; 1962.
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