Calciphylaxis is a condition of induced hypersensitivity in which tissues respond to challenge agents with local calcification. This article reports the first known case of diffuse calciphylaxis associated with acute myeloid leukemia resulting in death from hypoxic respiratory failure and refractory hypotension.
Calciphylaxis is a rare, poorly understood vasculopathic syndrome characterized by ischemia, thrombosis and necrosis due to calcification. Multiple sensitizing agents and subsequent challengers associated with calciphylaxis have previously been described. Prior case reports have reported the association of specific malignancies with calciphylaxis including metastatic breast cancer, multiple myeloma, Hodgkin’s lymphoma, chronic myelomonocytic leukemia, cholangiocarcinoma and malignnant melanoma. We present a case of newly diagnosed, acute myeloid leukemia with fatal hypoxic respiratory failure and refractory hypotension felt secondary to what was subsequently identified as diffuse calciphylaxis involving multiple organ systems. Clinicians caring for patients with acute myeloid leukemia should be aware of the possible association with diffuse, systemic calciphylaxis and consider this entity in patients with refractory hypotension and respiratory failure with no clear explanation. Though no therapeutic modality is clearly superior in treating calciphylaxis, treatments do exist that may limit and potentially reverse the damage caused by this disease process.
A 46 years old female with a past medical history of hypertension presented to an outside institution with a five-day history of flu-like symptoms and neck discomfort. In the emergency room the patient was febrile, hypotensive (62/44 mmHg) and had evidence of acute kidney injury (creatinine 4.7 mg/dL; reference 0.6 - 1.5 mg/dL) with a urinalysis suggesting urosepsis as the source of infection given a positive leukocyte esterase and nitrite component. The patient ultimately required norepinephrine blood pressure support as she was refractory to intravenous fluid resuscitation. A computed tomography (CT) scan of the abdomen and pelvis revealed a non-obstructive, 5 millimeter calculus in the left pelvis/proximal ureter, hepatomegaly and a prominent spleen. The patient was placed on antibiotics and taken for extracorporeal shock wave lithotripsy of the left proximal ureteral calculus with left ureter stent placement.
Furthermore, labs obtained upon presentation included a macrocytic anemia (hemoglobin 10.3 g/dL; reference range 12.0 - 16.0 g/dL and mean corpuscular volume 102.7 fl; reference range 80 - 100 fl) and thrombocytopenia (76 K/mcL; reference range 150 - 450 K/mcL) with normal white blood cell count and differential. Initial work up included a peripheral blood smear that demonstrated no schistocytes or leukoerythroblastic changes. Biochemical studies ruled out iron or vitamin deficiencies. At this juncture, the patient’s blood count abnormalities were felt to most likely reflect an underlying infection although there was no culture proven organism.
The patient initially responded to antibiotics and fluid resuscitation with a significant correction in her kidney function. However, she was found to have progressive thrombocytopenia and leukocytosis with a white blood cell count up to 21 K/mL. A sternal bone marrow aspiration was performed that revealed acute myeloid leukemia. She had a normal, female karyotype. Polymerase chain reaction demonstrated an insertion mutation in exon 12 of the nucleophosmin gene while demonstrating no mutations for FMS-like tyrosine kinase 3 and normal CEBPA mutation screen.
In conjunction with this diagnosis, the patient was found to have increasing neck discomfort associated with dysphagia. A CT scan of the neck revealed a 7 centimeter retropharyngeal abnormality felt to represent a fluid collection or abscess with infraglottic airway narrowing secondary to bilateral thyroid enlargement and lymphadenopathy. She was evaluated by a head and neck surgeon who felt this lesion to be secondary to leukemic infiltration as opposed to an infection. Therefore, incision and drainage was felt to be unnecessary. Soon thereafter, with subjective difficulty breathing, the patient was intubated prophylactically given the fear of evolving airway obstruction.
The patient was transferred to our hospital intubated, sedated and on broad spectrum antibiotics awaiting further management of her leukemia. At this point, she was still febrile and hypotensive requiring pressor support although all cultures remained negative. Her kidney function remained in the 1.5 - 1.6 mg/dL range throughout her stay at our facility. A repeat CT scan demonstrated a 10 centimeter bilateral neck mass arising from the thyroid and surrounding the trachea and esophagus (
of blasts with the same immunophenotype as previously identified in the peripheral blood and bone marrow, consistent with a myeloid sarcoma.
The patient was started on remission induction chemotherapy utilizing idarubicin and cytarabine. Though she was on broad spectrum anti-bacterial, anti-fungal and anti-viral therapy she required increasing pressor support during her hospitalization. Imaging suggested a consolidative pneumonia although no organisms were identified on successive bronchospies with bronchoalveloar lavage. Furthermore, the patient’s pulmonary status continued to decline with worsening hypoxemic respiratory failure. She ultimately passed away after her durable power of attorney made the patient comfort care only. A postmortem autopsy revealed diffuse calciphylaxis involving the lungs, scalp, subcutaneous soft tissues, peri-thyroid soft tissue and liver (Figures 2-4).
In 1962, Hans Selye originally defined calciphylaxis as a condition of induced hypersensitivity in which tissues responded to challenging agents with local calcifycation [
The precise pathogenesis of calciphylaxis is not clear. A recent review aiming to construct a pathogenic pathway looked at regulatory receptors and ligands that affect bone mineralization and resorption and how these could be affected by risk factors previously associated with calciphylaxis. The author felt that the final common pathway leading to vascular calcification was nuclear factor ĸ-B (NFĸB) activation and that “sensitizers” and “challengers” would directly or indirectly activate this pathway. The receptor activator of NFĸB (RANK) and its ligand (RANKL) are essential for normal bone development and bone mineral resorption. High NFĸB activity is associated with bone mineral loss. Conversely, osteoprotegerin (OPG) is an antaganost of RANK ligand, thereby inhibiting the RANK pathway. Increased expression of RANKL or deficient OPG may cause osteopenia, fractures and vascular calcification. The author felt that the etiology of malignancy induced extraosseous calcifycation could be secondary to the following: 1) tumor production of PTH or PTH-related peptide, vitamin D or various cytokines; 2) up-regulation of RANKL; 3) downregulation of OPG or potentially a combination of all of the above [
Kidney failure is the most important risk factor associated with the development of calciphylaxis as illustrated in a single institution cohort of 64 patients with calciphylaxis revealing 77% to be receiving dialysis for end-stage renal failure [
As outlined in a review article published in the Archives of Dermatology, several factors have been statistically associated with developing calciphylaxis in addition to those mentioned above, including liver disease, systemic corticosteroid use, increased erythrocyte sedimentation rate, elevated alkaline phosphatase, and elevated phosphorous level [
To date, there are no controlled, prospective studies to help dictate specific, efficacious therapeutic strategies in patients with calciphylaxis. Interventions have included cinacalcet [
This case is unique in that, to our knowledge and review of the literature, calciphylaxis has never been reported in association with acute myeloid leukemia. No clear pathophysiologic processes have been defined that lead to calciphylaxis. Multiple reports suggest it to be a complicated process requiring specific patient characteristics that may increase the likelihood of developing calciphylaxis in the face of certain physiochemical insults. Further research will be important to identify additional predisposing characteristics and general stressors that lead to the development of calciphylaxis. This knowledge will help in both intervention and treatment of this condition going forward. This case will raise awareness in physicians caring for patients with acute myeloid leukemia and this rare association.