Scott G. Satko, M.D.

Internal Medicine

Resident Grand Rounds

January 7, 1997

A 48 year old white female with end-stage renal disease secondary to type II diabetes mellitus was admitted to the NCBH Renal ward service 7/16/96 on transfer from an outside hospital, for evaluation and management of progressively worsening necrotic skin lesions. Prior to transfer, the patient’s working diagnosis was necrotizing myofasciitis as a complication of an inflammatory reaction to subcutaneous insulin injections. The patient had been complaining of lower abdominal pain for several weeks, and had undergone an abdominal wall biopsy one month earlier. This biopsy showed "fat necrosis with focal acute inflammation in the subcutaneous adipose tissue and focal calcification and ossification of small subcutaneous blood vessels," which was felt to be a "known possible complication of insulin injections."

PMH:

1. Type II diabetes mellitus, complicated by nephropathy and retinopathy

2. ESRD on 3x/wk. hemodialysis x 8 yrs.

3. Secondary hyperparathyroidism (intact-PTH 1970 units 6/96)

4. 3-vessel CAD, s/p AMI and PTCA of LAD 1992

5. CHF with mild systolic dysfunction (LVEF 46% 1994)

6. Hyperlipidemia

7. S/P cholecystectomy 2/95

8. GERD

Allergies: NKDA

Medications: Simvastatin, Ranitidine, Diltiazem CD, Glipizide XL, EC-ASA, Alprazolam, Calcium carbonate, Nitroglycerin SR

FH: positive for diabetes mellitus and CAD

SH: married; lives in VA; no EtOH or tobacco use

Physical Exam:

Vitals- T 98.2, P 91, R 24, BP 83/53

Gen- obese middle-aged white female

HEENT- poor dentition, otherwise unremarkable

Neck- supple, no JVD or adenopathy

Chest- clear

Cardiac- RRR, no m/r/g

Abd- obese, tender throughout, diminished bowel sounds

Extr- no edema, 2+/4 peripheral pulses

Neuro- nonfocal

Skin-several large (approx. 10 x 15 cm) indurated tender plaques with violaceous discoloration, calcification, and black eschar formation reaching from bilateral flanks to suprapubic region, around inferior border of panniculus; multiple smaller (approx. 1 cm) indurated nodules on chest and bilateral thighs

Labs:

Ca 9.0, Phos 4.3, BUN 21, Cr 3.0, Alb 2.4, ALP 409

WBC 8400, Hgb 11.0, Plt 196K, diff WNL

CXR: cardiomegaly, no infiltrates

AbdXR: extensive vascular calcification within abdomen

EKG: NSR 94, low voltage QRS, TWI V5-V6

Hospital Course:

After admission to NCBH, the patient was started on intravenous ampicillin/sulbactam for cellulitis vs. necrotizing fasciitis associated with calciphylaxis. Blood and wound cultures were obtained. Of these, only the wound cultures became positive, growing out E. coli, Enterococcus, Staph. epi, and Bacteroides fragilis. Antibiotic coverage was changed to ciprofloxacin after these results were obtained. A repeat intact-PTH level was 1065. Consultations were obtained from General Surgery (for possible parathyroidectomy), Pain Control, and Plastic Surgery and Dermatology (for confirmation of diagnosis and wound care management). Both panniculectomy and parathyroidectomy were recommended. During this hospitalization, the patient underwent two uneventful hemodialysis treatments.

On 7/19/96, the patient underwent total parathyroidectomy (with 3/3 glands removed) followed by panniculectomy. Pathology of excised tissue was consistent with secondary parathyroid hyperplasia as well as ulceration, fat necrosis, and focal vascular calcification of abdominal wall tissue, consistent with calciphylaxis.

Postoperatively, on the morning of 7/20/96, the patient became lethargic and hypotensive with systolic blood pressure 60-70s. She was aggressively treated with intravenous saline and dopamine and transferred to the MICU. Notable labs revealed Ca 6.8, Phos 4.3, CO₂ 12, with ionized Ca 0.78, for which she was given intravenous calcium chloride. Several minutes after transfer to the MICU, the patient suffered cardiopulmonary arrest. Despite 55 minutes of ACLS measures, the patient was unable to be resuscitated, and expired on hospital day #5, 7/20/96.

Autopsy revealed, as expected, evidence of calciphylaxis, with multiple plaque-like calcified lesions within the skin and subcutaneous tissues. Also noted was diffuse calcification of multiple blood vessels, including aorta and coronary, renal, celiac, mesenteric, and splenic arteries. Atrophic kidneys, cardiomegaly, splenomegaly, and severe passive congestion of the liver were noted. Additionally, the unexpected finding of a pericolic abscess adherent to the liver was noted, cultures of which grew out Staph. epi., non-Candida albicans yeast, and Clostridium ramosum.

Calciphylaxis is a condition in which diffuse vascular calcification occurs with resulting tissue necrosis. It is fairly rare, occurring in approximately 1% of all end-stage renal disease patients per year. In a 1991 survey of 150 U.S. nephrologists with 2-8 years of clinical experience each, only 20 of these physicians had managed a patient with calciphylaxis. Of these 20 nephrologists, each had only clinically managed one case during their career.¹⁹ The first known case was reported by Bryant and White in 1898, occurring in a six month old infant with renal failure associated with hydronephrosis.³ A pathophysiologic mechanism was first proposed by Selye in 1962, which will be discussed in further detail later.³¹ Calciphylaxis was not, however, clinically defined as a syndrome until 1976, when Gipstein, et al. reported a case series of 11 patients with chronic renal insufficiency affected with this condition.¹²

Skin manifestations

An early sign of ischemic tissue necrosis due to calciphylaxis is the appearance of painful, violaceous, mottled skin lesions similar in appearance to livedo reticularis. As calcium phosphate deposition continues, hard, painful, calcified subcutaneous nodules often begin to form. As the subcutaneous and dermal vasculature becomes occluded with calcium phosphate deposits, the skin and subcutaneous tissues begin to necrose, ultimately with blackened eschar formation.^1,7,15

There are two major patterns of distribution of ischemic tissue secondary to calciphylaxis. Although histologically and pathophysiologically both patterns are identical, the two major patterns differ greatly in prognosis. The most common, and unfortunately, also the most deadly pattern, is that of proximal distribution. This pattern involves the trunk as well as the extremities. 68% of patients with calciphylaxis, according to one study, have proximal involvement. 32% of patients are fortunate enough to have a distal pattern, defined as disease in the upper extremities distal to the elbows and/or disease in the lower extremities distal to the knees.⁴ This pattern of disease carries a far better prognosis.¹⁴ Overall, the thighs are the most common location for skin manifestations.⁹ On the thighs, lesions often occur in a "kissing" distribution.² In obese patients with disease of the abdominal wall, the inferior border of the panniculus is an extremely common site. Interestingly, the face and scalp are always spared.¹⁰ This appears to suggest that this condition is much more likely to occur in areas that are subjected to repeated trauma (from friction, etc.).

As calcium phosphate becomes deposited in the subcutaneous vasculature, stenosis, and ultimately occlusion of affected blood vessels will occur. Histologically, intimal fibrosis and mural calcification of the subcutaneous arteries and arterioles can be seen on skin biopsy. The other main histologic finding, as would be expected, is evidence of dermal and subcutaneous tissue necrosis due to an occluded blood supply.⁵

Calciphylaxis is observed more frequently in females, with a 2-3:1 female: male ratio.^2,4 The reason for this sex differential is not known. It is found much more frequently in Caucasians than African-Americans, Asian-Americans, or those of other races. Nearly all patients diagnosed with calciphylaxis have either end-stage renal disease or advanced chronic renal insufficiency, in the range of 91-100%, according to various case series reported in the literature.^4,8,10,25 Nearly all patients also are obese, with morbid obesity a rather common finding.² A common finding in one case series was poor nutritional status, as reflected by a low serum albumin. Another common finding in several patients in the same series was hypotension, often of several months duration prior to the initial diagnosis of calciphylaxis.² This finding is not well explained, but may be simply a reflection of overall poor medical and nutritional status.

A high percentage (83%) of patients with calciphylaxis are found to have diabetes mellitus, usually of long-standing duration, but this is easily explained by the high frequency of diabetes in the population of end-stage renal disease patients.⁸ As would be expected, hyperparathyroidism is another extremely common associated finding (83%), as well as hyperphosphatemia (63%). Interestingly, however, hypercalcemia is a much less frequent association, found in only 20% of patients with calciphylaxis. Even more astonishing, however, is the fact that an elevated calcium-phosphate product (defined as > 70 mg²/dl²) is found with rather low frequency, only 33%, according to one series.⁴ 38% of patients with calciphylaxis have received prior renal transplants, and 49% (which includes nearly all patients in the former group) have received recent corticosteroid therapy.^4,11 This suggests that corticosteroids may be inducing agents which increase a patient’s susceptibility toward calciphylaxis, a hypothesis which will be discussed in further detail later.

As noted earlier, calciphylaxis is most commonly found in patients with end-stage renal disease and associated secondary hyperparathyroidism. Less frequently, it can be seen with other conditions associated with hypercalcemia, such as primary hyperparathyroidism, vitamin D intoxication, milk-alkali syndrome, rickets, and malignancy.¹⁶

Calciphylaxis was first studied in the laboratory by Selye in the early 1960’s. After studying this condition extensively in rats, Selye proposed a pathophysiologic mechanism in 1962.³¹ For calciphylaxis to occur, it appeared that other conditions must be met, rather than simply elevated serum calcium and/or phosphate levels. Were elevated levels of these two electrolytes sufficient to produce this syndrome, calciphylaxis should be found much more frequently in the chronic renal insufficiency and end-stage renal disease populations. Instead, calciphylaxis is fairly rare, seen in approximately 1% of end-stage renal disease patients per year.

Selye proposed that in order for the phenomenon of calciphylaxis to occur, three separate conditions must be met. First, a subject must be exposed to a sensitizing agent. Second, a critical time period must pass. Third, after this critical time period passes, a subject must be exposed to a specific challenging agent.^29-31

Selye proposed several different substances as potential sensitizing agents. The most common sensitizing agent seen clinically is parathyroid hormone. Other proposed agents are Vitamin D (in any of its forms, i.e., vitamin D₂, vitamin D₃, or dihydrotachysterol (DHT)), elevated serum calcium, and elevated serum phosphate. It is important to realize that the presence of one or more of these sensitizing agents alone is insufficient to produce the phenomenon of calciphylaxis.^29-31

Next, a critical time period must pass, which is usually greater than 24 hours. In laboratory rats, Selye found that introduction of a known challenging agent sooner than 24 hours after administration of a known sensitizing agent often failed to produce calciphylaxis. Conversely, administration of the challenger after this critical time period had been allowed to pass usually always produced calciphylaxis in his subjects.^29-31

Finally, exposure to a challenging agent is necessary. Proposed challenging agents include corticosteroids and other immunosuppressants, exogenous albumin, and metallic salts, among many others. Additionally, local tissue trauma was found to be a common challenging mechanism for producing calciphylaxis.^13,29-31 Several of these mechanisms have been observed to occur clinically in human subjects, while others have only been noted in experimental animal subjects. The inclusion of corticosteroids and other immunosuppressants among the list of challenging agents helps to explain why over one-third of cases of calciphylaxis, according to one series, are found to occur in post- renal transplant patients. Many patients on hemodialysis require occasional intravenous albumin infusions; however, it is not clear whether this proposed mechanism for calciphylaxis actually occurs clinically. The administration of metallic salts in the form of intravenous iron injections has been associated clinically with the occurrence of calciphylaxis in humans.²⁴ Additionally, an association between calciphylaxis and the presence of an iron overload state secondary to multiple blood transfusions has been demonstrated.²⁷

Another group of authors, Mehta, et al., have proposed acquired protein C deficiency as another possible etiology of calciphylaxis in certain patients with end-stage renal disease. This proposed mechanism for calciphylaxis is similar to the mechanism responsible for producing warfarin-associated skin necrosis. Mehta, et al., observed that skin biopsies obtained from patients with calciphylaxis were histologically similar to biopsies obtained from patients with warfarin-associated skin necrosis, both revealing thrombotic occlusion of venules.²¹ Additionally, although protein C antigen levels were observed to be similar in patients with end-stage renal disease and calciphylaxis and control groups without calciphylaxis and with and without renal failure, protein C activity was significantly (p < 0.01) decreased in the former group.²¹

Levin, et al. proposed a mathematical formula to help identify patients at high risk for the syndrome of calciphylaxis. This model was derived using 20 cases of calciphylaxis from the literature between 1968 and 1990 and 54 control cases of end-stage renal disease patients with secondary hyperparathyroidism but not calciphylaxis. According to the authors, this model has a sensitivity of 80%, specificity of 92%, positive predictive value of 66%, and negative predictive value of 96%, assuming a 1% prevalence rate of calciphylaxis in end-stage renal disease patients. The proposed formula to quantitate the degree of risk is as follows:

2 x [(0.0806 x Ca x Phos) - 5] x ALP x PTH ratio,

where Ca = serum calcium in mg/dl, Phos = serum phosphate in mg/dl, ALP = serum alkaline phosphatase in IU/ml, and PTH ratio = ratio of parathyroid hormone level to the upper limit of normal in a given laboratory.¹⁹

An example of how this formula works can be illustrated by plugging in the data from the case presentation discussed earlier:

Ca = 9.0

Phos = 4.3

ALP = 409

PTH ratio = 1065 / 46 = 23.15

2 x [(0.0806 x Ca x Phos) - 5] x ALP x PTH ratio =

2 x [(0.0806 x 9.0 x 4.3) -5] x 409 x 23.15 =

-35,616

Levin, et al., used +1000 as a cutoff value, above which patients were deemed to be at high risk for developing calciphylaxis.¹⁹ All values below this, including negative values, as in the case illustrated above, were deemed to indicate a relatively low level of risk for developing calciphylaxis. It is interesting that using this mathematical model, the patient discussed above, who had histologically-confirmed calciphylaxis on two separate skin biopsies obtained both premortem and postmortem, would be placed in the low-risk category. This can be explained by an apparent flaw in this model. Although this model appropriately recognizes the importance of an elevated serum parathyroid hormone level as a risk factor for calciphylaxis, it unfortunately weights elevated serum calcium and phosphate levels much more greatly. Using this formula, any patient with a calcium-phosphate product less than 62 mg²/dl² would have a calculated risk level less than zero, placing them in a low-risk category. This is at odds with data discussed earlier, which shows that only one-third of patients with calciphylaxis are found to have an elevated calcium-phosphate product.⁴

Differential diagnosis

• Vasculitis
• Scleroderma / CREST syndrome
• Cryoglobulinemia
• Systemic lupus erythematosus
• Polyarteritis nodosa
• Sjogren’s syndrome
• Mixed connective tissue disease
• Henoch-Schonlein purpura
• Cholesterol emboli syndrome
• Atherosclerotic peripheral vascular disease
• Cellulitis
• Weber-Christian syndrome

The differential diagnosis of calciphylaxis is extremely broad and encompasses many entities associated with ischemic tissue necrosis related to vascular occlusion.^1,4,25,26 Any autoimmune disease which affects the vascular system can be confused clinically and histologically with calciphylaxis. Most of the autoimmune diseases, however, are easily differentiated from calciphylaxis by the presence of seropositivity for the associated antibody, i.e., anti-Scl-70 and antinucleolar antibody with scleroderma, ANA and anti-ds DNA with systemic lupus erythematosus, and anti-SSA/SSB with Sjogren’s syndrome. Cryoglobulinemia can easily be distinguished from calciphylaxis by the presence of serum cryoglobulins.¹ Polyarteritis nodosa and Henoch-Schonlein purpura usually can be identified by their distinguishing histological characteristics. Cholesterol emboli syndrome usually can be identified by appropriate history and physical examination findings. Atherosclerotic peripheral vascular disease, although extremely common in the patient population susceptible to calciphylaxis, can usually be differentiated by the presence of diminished peripheral pulses in this condition.⁴ Calciphylaxis is much less likely to cause occlusion of the large peripheral arteries, and so diminished peripheral pulses would not be an expected physical finding. Cellulitis is usually easily distinguished given the clinical setting, as well as appropriate historical and physical findings. It should be noted, however, that the two conditions, cellulitis and calciphylaxis, commonly occur together. Areas of necrotic tissue resulting from calciphylaxis are extremely likely to become secondarily infected.

Treatment of calciphylaxis involves a combination of medical and surgical interventions. Despite the most aggressive treatment, however, this condition is associated with an extremely high mortality rate. Because of this, it is imperative that the condition be recognized and aggressively treated early in its course. Any serum electrolyte abnormalities, especially those involving calcium and phosphate, should be normalized as much as possible. Hyperphosphatemia can be treated with phosphate-binding agents such as oral calcium carbonate. In the case of associated hypercalcemia or an elevated calcium-phosphate product, aluminum-containing phosphate binders can be used. Aggressive wound care is absolutely imperative, as the most common cause of morbidity and mortality in calciphylaxis patients is sepsis from uncontrolled infection of necrotic tissue. Systemic antibiotics are frequently necessary, with choice of antibiotic dictated by clinical setting and location of infection. Debridement and excision of necrotic tissue is often necessary.²⁵ Most authorities agree that urgent parathyroidectomy is indicated for affected patients, although there is some disagreement as to whether this procedure truly improves mortality.^{1,6,11,14-18,23,25,27} One group of authors suggests that bisphosphonates may be a useful therapy for calciphylaxis.⁴ Another group describes the successful use of hyperbaric oxygen therapy with subsequent resolution of skin lesions.³² Given the extremely high mortality rate regardless of modality of therapy used, it is apparent that more research into pathophysiology and treatment of this deadly condition must be performed.

As mentioned repetitively above, the prognosis for patients with calciphylaxis remains extremely poor, despite the fact that this disease has been studied extensively for nearly four decades. Patients with purely distal lesions, i.e., only upper extremity lesions distal to the elbows and/or lower extremity lesions distal to the knees, have a far better prognosis than those with more proximal lesions. While the overall mortality rate is approximately 60%, the rate for patients with purely distal disease is somewhat lower at 32%, according to one study.^16,25 The group of patients affected by proximal manifestations, however, suffers a more dismal mortality rate of 86%, according to the same study.^25,26 Most patients who die from calciphylaxis actually succumb to sepsis occurring as a result of uncontrolled wound infections.^1,9,25 It is important to realize that patients have very little chance of improvement once advanced complications such as sepsis have occurred.²⁵ For this reason, it is necessary to recognize calciphylaxis early in its course, so that complications can be either prevented or aggressively treated.

Summary

• Definition: diffuse calcification affecting the vasculature with associated ischemic necrosis of peripheral tissues
• Frequency: rare; incidence approximately 1% of ESRD patients / year
• Most common associated conditions: end-stage renal disease, secondary hyperpara-thyroidism
• Broad differential diagnosis: autoimmune diseases, vasculitides, atherosclerotic and cholesterol-associated diseases
• Treatment: normalization of electrolytes, aggressive wound care, parathyroidectomy
• Prognosis: distal disease better than proximal; however, extremely poor regardless of site!

REFERENCES