Other less frequent signs and symptoms consist of anaemia, fever, weight loss, night sweats, infection, bleeding, synovitis, lymphadenopathy, skin rashes, pleural effusion, pericardial effusion and peritoneal effusion. Cause
Although the cause of CMML is unknown, environmental carcinogens, ionising radiation and cytotoxic agents may have a role in causing disease. Approximately one third of cases of MDS with a monocyte count of >10% and <1x109/L will progress to CMML. Pathogenesis
With a high rate of Ras mutation in CMML, deregulation of this signalling pathway has been linked to the pathogenesis of the disease. Tumour necrosis factor, GM-CSF, interleukin-3, interleukin-4, interleukin-6, and interleukin-10 may have a role in hyperproliferative CMML cells. These cytokines can stimulate the growth of CMML in vitro. Hypermethylation of cytosine residues (usually in the promoter regions of genes) occurs in many malignancies to regulate gene expression. One commonly hypermethylated gene in CMML is p15INK4b, a gene involved in cell cycle regulation. Genetic mutations
Clonal genetic abnormalities are common in CMML but they are not specific for diagnosis of the disease. The most common found are the 8+, −7/del (7q) and structural 12p abnormalities. KRAS and NRAS are mutated in 25–40% of the cases of CMML. The Jak2 V617F mutation is found in 10% of cases. Mutations in transcription factors such as RUNX1, CEBPA, NPM1 and WT1 have been found in up to 30% of cases. Mutations of CBL are found in approximately 5–18% of cases. Mutations in the TET2 gene are found in approximately 40–50% of CMML.
Differential
It may not be possible to tell the difference between beta blocker toxicity and calcium channel blocker overdose based on signs and symptoms. Management
The medical management of CCB toxicity may be difficult. It may not improve with the usual treatments used for a low blood pressure and a slow heart rate. In those who have no symptoms or signs six hours following taking an immediate release formulation and 24 hours after taking an extended release formulation need no further medical treatment. Detoxification
Activated charcoal is recommended if it can be given within an hour or two of taking the calcium channel blockers. In those who have taken an extended release formulation of a CCB but are otherwise doing fine, whole bowel irrigation with polyethylene glycol may be useful. Causing vomiting by the use of medications such as ipecac is not recommended. Insulin
High doses of intravenous insulin with glucose may be useful and are a first line treatment in overdoses. As this treatment may cause a drop in blood sugar and blood potassium levels, these should be monitored closely. Other
Intravenous calcium gluconate or calcium chloride is considered a specific antidotes. Slow heart rate can be treated with atropine and sympathomimetics. Low blood pressure is treated with vasopressors such as adrenaline.There is tentative clinical evidence and good theoretical evidence of the benefit of lipid emulsion in severe overdoses of CCBs. Methylene blue may also be used for those with low blood pressure that does not respond to other treatments.