Hypercalcemia of malignancy occurs as the result of direct bone metastasis and via humoral mechanisms such as parathyroid hormone-related protein (PTHrP) or 1,25-dihydroxyvitamin D mediated pathways
ectopic secretion of parathyroid hormone (PTH) has been implicated
Hypercalcemia due to osteolytic bone lesions is common in multiple myeloma, leukemia, and breast cancer
Humoral hypercalcemia is predominant in squamous cell, renal cell and ovarian cancers, and lymphomas are associated with 1,25-dihydroxyvitamin D mediated hypercalcemia
20% of cases of hypercalcemia of malignancy and is frequently encountered in multiple myeloma, metastatic breast cancer, and to a lesser extent in leukemia and lymphoma
Physiologic bone turnover requires the complementary activity of osteoblasts – mesenchymal stem cell-derived bone-forming cells – and bone-resorbing cells of monocyte and macrophage lineage known as osteoclasts
In local osteolytic hypercalcemia, the RANKL/RANK interaction results in excessive osteoclast activation leading to enhanced bone resorption and thus hypercalcemia
In addition, osteoclast activation is also mediated by malignancy secreted cytokines, including interleukin-1, initially termed “osteoclast stimulating factor”
Macrophage inflammation protein 1-alpha (MIP 1-alpha)
hypercalcemia is through extra-renal 1,25-dihydroxyvitamin D (calcitriol) production
1% of cases
increased production of 1,25-dihydroxyvitamin D occurs nearly exclusively in Hodgkin and non-Hodgkin lymphoma with case reports of the same in ovarian dysgerminoma
1-α-hydroxylase in the kidney, a process regulated by PTH
in 1,25-dihydroxyvitamin D induced hypercalcemia, malignant cells likely recruit and induce adjacent macrophages to express 1-α-hydroxylase, converting endogenous calcidiol into calcitriol.31 Calcitriol then binds to receptors in the intestine leading to heightened enteric calcium reabsorption with resultant hypercalcemia
this mechanism of disease is best conceptualized as an absorptive form of hypercalcemia
Ectopic production of PTH by malignant cells has been described in a handful of cases involving cancer of the ovary and lung, as well as neuroendocrine tumors and sarcoma
primary hyperparathyroidism and malignancy comprising nearly 90% of cases of hypercalcemia
an initial panel consisting of PTH, PTHrP, phosphorus, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D should be obtained
Lymphoma, a hypercalcemia due to 1,25-dihydroxyvitamin D mediated pathways, is implied by elevations in 1,25-dihydroxyvitamin D without concomitant elevations in 25-hydroxyvitamin D. In such cases, PTH is low and PTHrP undetectable
Treatment of hypercalcemia of malignancy is aimed at lowering the serum calcium concentration by targeting the underlying disease, specifically by inhibiting bone resorption, increasing urinary calcium excretion, and to a lesser extent by decreasing intestinal calcium absorption
mildly symptomatic disease
marked symptoms
hydration with isotonic fluid (if admitted), avoidance of thiazide diuretics, and a low-calcium diet
denosumab
Denosumab is an RANKL antibody that inhibits osteoclast maturation, activation, and function
administered zoledronic acid (4 mg). Prednisolone (1 mg/kg/day) was started and simultaneously, she was administered first cycle of ABVD (Adriamycin: 25 mg/m2, Bleomycin: 10 U/m2, Vinblastine: 6 mg/m2 and Dacarbazine: 375 mg/m2), which led to normalisation of serum calcium levels over 4 days and improvement in her hemoglobin levels
Etiology of anemia in Hodgkin’s lymphoma is multifactorial. Anemia of chronic disease, decreased red cell survival, infiltration of bone marrow by tumor and marrow suppression by chemotherapy/radiotherapy are the common mechanisms
Our case had only a transient response to steroids and chemotherapy. Therefore, she was treated with Rituximab which brought hemolysis under control
Mechanism of hypercalcemia in HL has long been suggested to involve extra-renal activation of 1α-hydroxylase leading to production of 1, 25(OD)2 Vitamin D3 or Calcitriol, an active metabolite of Vitamin D, which leads to increased re-absorption of calcium and phosphate from intestine, increased osteoclast activation and bone resorption as well as increased phosphate re-absorption in renal tubules
Hypercalcemia of malignancy involves three mechanisms: 1. Humoral hypercalcemia mediated by PTHrP—seen in solid tumors like breast cancer and adult T cell leukemia/lymphoma (ATLL), 2. Direct osteoclast mediated bone resorption due to bony metastasis—seen in solid tumors and multiple myeloma, 3. Calcitriol mediated hypercalcemia—seen in Hodgkin’s and non-Hodgkin’s lymphoma as well as granulomatous disorders like tuberculosis, sarcoidosis, leprosy and disseminated Candidiasis
Hypercalcemia in HL is rare and its incidence has been reported as 0.9, 1.6 and 5.4 % in different series
The source of 1α-hydroxylase in HL has been postulated as monocytes and macrophages infiltrating the tumor akin to tuberculosis or sarcoidosis and is stimulated by IFN-γ secreted by T-lymphocytes
Like sarcoidosis, patients with HL exhibit increased sensitivity to Vitamin D supplements and sunlight, which have been found to precipitate hypercalcemia in these patients
Classical biochemical profile in Calcitriol mediated hypercalcemia include: an elevated calcium, normal/slightly elevated phosphate, normal 25(OH) Vitamin D, suppressed PTHrP and PTH, elevated Calcitriol and a normal/increased tubular reabsorption of phosphate
not been associated with a poorer prognosis and tends to subside after treatment of the underlying disease
play a role during the initial chemotactic response of neutrophils shortly after infection
following vitamin C supplementation, a 20% increase in neutrophil chemotactic activity was observed
also contributes to the phagocytosis and killing of microbes by neutrophils
low levels of vitamin C occurring in high-stress situations
maturation, proliferation, and viability of T cells have all been shown to be upregulated by the presence of normal physiologic concentrations of vitamin C
Vitamin C has been shown to directly affect the number of Igs released from B cells
vitamin C among healthy young adult males showed a significant increase in serum levels of IgA, IgG, and IgM
effects of high-dose vitamin C on cytokine levels in cancer patients, finding decreased amounts of the cytokines Interleukin-1 alpha (IL-1 alpha), IL-2, IL-8, and tumor necrosis factor-alpha (TNF-alpha) after high-dose vitamin C infusion
when vitamin C was supplemented with vitamin E in healthy adults, it increased the production of cytokines IL-1 beta and TNF-alpha
vitamin C acts to modulate the levels of cytokines to prevent them from fluctuating in either direction
vitamin C also acts as an important antioxidant to the cells of the immune system.
human leukocytes, neutrophils, in particular, possess the ability to transport the oxidized form of vitamin C across its membrane to use as a defense mechanism against ROS produced during an immune response
Vitamin C also can recover other endogenous antioxidants in the body such as vitamin E and glutathione, returning them to their active state
vitamin C can decrease the activation of NF-kB
can reduce harmful nitrogen-based compounds such as N-nitrosamines and nitrosamides, both of which are carcinogenic
subjects taking oral vitamin C supplementation saw a 60% to 90% reduction in oxidative stress compared to a placebo control
subjects infused with vitamin C alone had a 516% increase in glutathione levels compared to subjects not provided the 500 mg daily supplementation
hydroxylating proline and lysine
mature and stabilize the tissue of a healing wound
healing
oral surgery
improved soft tissue regeneration
vitamin C increases the mRNA levels of type I and type III collagen in the human dermis
Studies have demonstrated that those with low levels of vitamin C are at a significantly higher risk of respiratory infection compared to those with normal levels
viral cold duration was reduced by about 8% in adults and 13.5% in children using prophylactic daily doses of 200 mg of oral vitamin C
prophylactically supplementing vitamin C decreases the risk of infection with respiratory viruses such as the common cold
combined with probiotics, oral vitamin C supplementation showed a 33% decrease in the incidence of respiratory tract infections in preschool-age children [
high-dose oral supplementation of vitamin C managed to prevent or reduce symptoms if taken before or just after the onset of cold- or flu-like symptoms
improvements in oxygen saturation and decreased IL-6 levels (a marker of inflammation) in the treatment group compared to the control group
8 g doses of oral vitamin C
there is a negative correlation between age and serum levels of vitamin C
Patients with COVID-19 will likely also experience depletion in serum levels of vitamin C as a direct result of the upregulation of the immune system to combat the infection
Colunga et al. suggested that oral vitamin C can be combined with oral Quercetin, an antiviral flavonoid, to improve Quercetin’s ability to block viral membrane fusion of SARS-CoV-2
high doses of 1-2 g/day of oral vitamin C could prevent other upper respiratory infections
It appears vitamin C supplementation by itself does not provide a striking benefit in preventing COVID-19 infection for those without a deficiency
Flawed statement. What is normal? Vitamin D.
Many variables effect levels and dose, including the two compartment kinetics and absorption.
Hiedra et al. were able to show decreases in inflammatory biomarkers, such as D-dimer and ferritin
some evidence to support that prophylactic use of vitamin C helps reduce the severity of respiratory infection symptoms once a subject has already been infected
oral vitamin C in combination with zinc provided the largest amount of antibody titers 42 days
linear relationship between days of vitamin C therapy and survival duration
other studies were unable to find any definitive improvement concerning therapy with vitamin C
Either these studies are designed to fail or the authors are lacking some basic understanding of pharmacokinetics and pharmacodynamics with vitamin C.
Fowler et al. aimed to see if a high-dose vitamin C infusion would benefit patients affected by ARDS, but they were unable to conclude that vitamin C infusion, compared to a placebo, could decrease vascular inflammation and damage in ARDS
They are kind of make the point from my earlier note.
continuous vitamin C infusion at a rate of 60 mg/kg/day for four days decreased the need for mechanical ventilation and vasopressor use but had no significant effect on overall mortality
Again, designed to fail or ignorance designed the study which failed
Carr et al. suggested that high-dose IV vitamin C is most effective when treating sepsis as septic patients receiving the normal daily recommendations through diet still showed decreased vitamin C levels
High-dose IV vitamin C treatment has also been shown by Kakodkar et al. to decrease syndecan-1, an endothelial glycocalyx that contributes to mortality in septic patients
combined with hydrocortisone and thiamine, septic patients treated with 1.5 g of IV vitamin C every six hours showed a distinct decrease in their SOFA scores and none of the patients treated developed organ failure
combined with hydrocortisone and thiamine, septic patients treated with 1.5 g of IV vitamin C every six hours showed a distinct decrease in their SOFA scores and none of the patients treated developed organ failure
reduced overall mortality
reduced overall mortality
propose the use for high-dose vitamin C to aid in the treatment of septic shock-induced hypotension
treatment of severe sepsis using a high dose (up to 200 mg/kg/day) of IV vitamin C was explored in phase I, a double-blind, randomized, placebo-controlled trial by Fowler et al. [75]. Their findings included a reduction in SOFA scores and decreased vascular injury compared to a placebo control group, all while showing minimal adverse side effects