Calciphylaxis is a rare, potentially life–threatening syndrome characterized by increased tissue sensitivity to calcium. The development of calcifilactic reactions leads to a rapid progression of calcification, thrombosis of small and medium arteries, ischemia of the skin and subcutaneous tissue, internal organs. The tissue areas covered by the pathological process are sharply painful, gradually necrotize and ulcerate. Diagnostics includes the performance of X-rays of the affected areas, histological examination. Conservative treatment involves the correction of mineral metabolism, surgical – excision of the affected areas within healthy tissues.
The term “calciphylaxis” was coined by the Canadian researcher Hans Selye, who created an experimental model of calcifylactic reactions on animals. In the English-language literature, the term “calcifying uremic arteriopathy” is used to define the disease. The syndrome is diagnosed mainly in patients of the older age group with end-stage renal failure. The incidence of pathology among patients on dialysis is, according to various data, from 1 to 4%. 64% of them die in the first year after the appearance of clinical signs of pathology from sepsis or rapidly progressing multiple organ failure.
The role of calciphylaxis reactions in dermatology has not been sufficiently studied. In his works, G. Selye considered sensitization to calcium as a protective reaction, during which lime deposition can increase the resistance of tissues to the effects of damaging factors. A combination of several reasons leads to the development of the pathological process:
- Severe kidney damage. The disease develops in dialysis patients and in patients who have undergone kidney transplantation surgery. It is based on a violation of the metabolism of mineral salts in the body, primarily calcium and phosphorus, which is aggravated by the use of dialysis media with calcium salts in the composition.
- Secondary hyperparathyroidism. Violation of the function of the parathyroid glands against the background of renal insufficiency is observed quite often. A change in the concentration of parathyroid hormone disrupts the balance of bone and extra-bone metabolism of calcium and phosphates, accelerates bone resorption, promotes the release of minerals into the blood, stimulates the deposition of salts in the walls of blood vessels.
Increases the likelihood of the formation of calcifilactic reactions diabetes mellitus, obesity, the use of glucocorticosteroids, immunosuppressants, anticoagulants such as warfarin, polyneuropathy, endocrine diseases, monoclonal gammapathy. The more risk factors a patient has, the faster the disease progresses, the more difficult the treatment and the worse the prognosis.
The development of the pathological process is based on two phenomena: sensitization to calcium and the effect of so-called “resolving” factors that provoke the deposition of calcium salt in the vascular wall. A local increase in the concentration of minerals in the intima of the vessels leads to a change in the phenotype of the cells of the vascular wall. Smooth muscle cells gradually degenerate into bone tissue cells. Arteries lose elasticity, their lumen narrows. Arterial stenosis progresses rather slowly. At this stage, there are no external manifestations of the disease or they are insignificant.
The development of acute painful ischemic purpura is associated with thrombosis. The appearance of blood clots is facilitated by slowing blood flow in stenosed arterioles, damage to the inner lining of blood vessels, hypercoagulation. Progressive circulatory disorder causes tissue ischemia and their subsequent necrosis.
The pathological process mainly captures the posterior and lateral surfaces of the shins, buttocks, abdomen, forearms and hands, in men – the penis. The skin in the affected area pales, becomes much denser to the touch, sometimes acquires a marble hue. The foci are sharply painful. Intense painful sensations can make it difficult for the patient to move. With the defeat of the calves, patients cannot walk, they are forced to move in a wheelchair. Opioid analgesics may be needed to relieve pain. In diabetic polyneuropathy, pain may be absent.
Gradually, tissues that are deficient in oxygen and nutrients die off with the formation of ulcers. An intermediate stage in the formation of an ulcer is a bubble with a sluggish cap filled with serous contents with an admixture of blood. When the bubble bursts, the eroded surface is exposed. The ulcers are deep, penetrate into the subcutaneous tissue. A scab is forming along the edges of the skin wound. The skin around the ulcer gradually changes color from marble-white to dark red, bluish or purple. Necrosis is characterized by black coloration of the skin. The affected area is steadily expanding and can capture entire anatomical areas. The process progresses over several weeks or months.
A rather rare variant of calciphylaxis is the involvement of internal organs in the pathological process, in particular, the terminal parts of the large intestine. With this form of the disease, foci of ischemia form in the abdominal cavity, which is accompanied by the appearance of intense abdominal pain, bleeding from the intestines.
The main complications of calcifying arteriopathy are sepsis, progressive multiple organ failure, tissue necrosis requiring necrectomy. In the absence of medical care, gangrene of the fingers, penis can end with their spontaneous amputation. In 1-2% of cases, cardiac arrest occurs due to damage to the coronary arteries. In the intestinal form of pathology, bleeding from the gastrointestinal tract forces doctors to perform abdominal operations one after another, remove necrotic parts of the intestine, restore intestinal patency. Taking into account the patient’s end-stage renal failure and other severe concomitant pathology, the outcome of large-volume surgical interventions is not always favorable.
It is difficult for a dermatologist to diagnose calciphylaxis. Doctors of other specialties are often involved in the diagnosis: a surgeon, a nephrologist, an oncologist, an endocrinologist. At the initial stages, the disease resembles a number of other pathological processes in its manifestations, so it is necessary to conduct several different diagnostic tests and evaluate their results in aggregate:
- X-ray examination. X-rays of the lower legs, thoracic and abdominal cavities are performed. Vessels with lime deposits are clearly visible on radiographs. In the thoracic cavity, calcification of the aorta is detected, in the abdominal cavity – mesenteric vessels, arteries that supply blood to the liver and other organs. In controversial or unclear cases, they resort to performing computed tomography.
- Kidney biopsy. In the samples of kidney tissue taken for histological examination, nephroangiosclerosis and calcinosis are detected. Lime deposits are located mainly in the middle layer of the vascular wall. The study is used for early diagnosis of pathology, to clarify the condition of the kidneys. Histological examination of the skin is uninformative, since changes in it are nonspecific.
- Determination of the level of calcium (Ca) and phosphorus (P). Serum concentrations of Ca and phosphates are used to assess the risk of calcification of soft tissues, blood vessels and kidneys with an already established diagnosis. Calcifilactic crisis can develop with a low product of Ca and P concentrations . High rates are not always a sign of calciphylaxis.
- Study of the level of parathyroid hormone. Calcium metabolism in the body is regulated by hormones of the parathyroid glands. The development of pathology is usually associated with secondary hyperparathyroidism, which develops in patients with renal insufficiency. But a decrease in the function of the parathyroid glands can negatively affect mineral metabolism.
In dermatology, local manifestations of calciphylaxis must be differentiated with dystrophic and metastatic calcification of the skin, systemic scleroderma, the development of lightning-fast purpura in DIC syndrome, warfarin (heparin) necrosis, some types of vasculitis. In surgery, differential diagnosis is performed with putrefactive phlegmon, thromboembolism of large arteries.
The effect of the therapy can be obtained only with an integrated approach. Medical tactics may vary depending on the patient’s condition, concomitant pathologies, and the rate of progression of ischemia. As a rule, the doctor has to take into account several serious diseases that the patient has at once, each of which can lead to rapid decompensation of the condition and death. The main methods of treatment include:
- Correction of the therapy of the underlying disease. Any drugs that provoke lime deposition are excluded: iron preparations, vitamin D, anticoagulants, corticosteroids, etc. If the medications cannot be canceled completely, their dose is adjusted. The number of hemodialysis procedures increases from 3 to 5 per week. The ionic composition of dialysis solutions is changing in order to reduce the concentration of minerals in the blood.
- Treatment of wounds. To prevent the spread of a purulent infection in the tissues of the ulceration area, antiseptic solutions are treated, ointments with antibiotics are applied. The dead fragments are surgically removed. Due to the high probability of penetration of bacteria into the blood with the development of sepsis, broad-spectrum antibiotics are preemptively prescribed.
- Subtotal resection of the parathyroid glands. The method is used in cases when lime deposition in the vessels is detected at the early stages of the formation of the pathological process, and according to the biochemical analysis of blood, there is a sharp increase in parathyroid hormone in the blood. In the later stages of the disease, the benefits of surgery are usually minimal.
- Physical therapy. Hyperbaric oxygenation procedures, which are prescribed in repeated courses, allow to accelerate the healing of ulcers. A good effect can be obtained from oxygen cocktails. Increasing the oxygen concentration in tissues supports cell viability, stimulates the healing process, which increases the effectiveness of conservative and surgical treatment.
- Appointment of bisphosphonates. It is an experimental method. The main property of bisphosphonates is to prevent the loss of minerals by bone tissue. The less calcium is washed out of the bone, the lower its concentration in the blood serum. There are reports of the effective use of one of the pamidronic acid group drugs for the treatment of calciphylaxis in patients suffering from severe renal insufficiency.
- Symptomatic treatment. It is assigned individually in each specific case. It may include weight loss in obesity, control and correction of blood sugar levels in diabetes mellitus, the appointment of a tissue plasminogen activator in patients with lower limb vein thrombosis, sodium thiosulfate to reduce the calcium content in the blood, infusion therapy to eliminate intoxication resulting from tissue breakdown.
Prognosis and prevention
It is impossible to eliminate the cause of calciphylaxis, but it is possible to balance mineral metabolism in such a way as to prevent the loss of salt crystals from the blood and at the same time not provoke osteoporosis in patients suffering from impaired renal function. The prognosis and survival of patients is higher in cases of early detection of pathological changes in the vessels before the development of clinical symptoms (ischemia and ulceration), compensated condition of patients for other diseases they have (diabetes mellitus, hypertension, etc.). Methods for the prevention of calciphylaxis have not been developed. It is recommended to seek medical help in a timely manner, take medications prescribed by a doctor, undergo the necessary examinations and procedures.