An oft-mentioned adage in medicine is that "uncommon presentations of common diseases are more common than common presentations of uncommon diseases"; nowhere does this hold truer than in the field of emergency medicine. Yet, it is wise to keep in mind that during the course of his or her career, the emergency physician will almost certainly have to contend with more than a few such "uncommon diseases". Consider this patient; as one might appreciate, nausea, vomiting and malaise are both extremely common symptoms, while also being highly nonspecific; the majority of such patients presenting to the emergency department are eventually found to have gastroenteritis. However, these symptoms can also be caused by a formidable array of serious diseases ranging from infection to malignancy; in this particular patient, the presence of an unexplained hyperkalemia is a strong pointer that something is very wrong. In patients in whom an unexpected hyperkalemia is detected, the first step should be exclusion of pseudohyperkalemia (i.e. artifactual elevation of the serum potassium level due to in vitro cell-lysis). To do this, one should exclude significant leukocytosis (> 100,000/mm3) or thrombocytosis (> 500,000/mm3) via a full blood count; in addition, the serum electrolyte assay may need to be repeated, for re-confirmation. If the presence of true hyperkalemia is established (as in this patient), the next step should be immediate assessment of the patient for clinical signs of toxicity (such as palpitations, an irregular pulse, weakness, or focal neurological signs), as well as for ECG changes. Fortunately, there is no evidence of toxicity in this patient (for now at least). Patients with mild hyperkalemia (i.e. a potassium level between 5.5 to 6.0 mEq/L) and no features of toxicity do not necessarily require immediate potassium lowering measures such as nebulization with beta-2-agonists or cardioprotection with calcium gluconate; therapy with sodium or calcium resonium is sufficient. However, all patients with hyperkalemia (whether mild, moderate or severe) should receive continuous ECG monitoring, and close observation. The next step in his evaluation should be determination of the likely underlying cause. True hyperkalemia is caused by one (or more) of three main mechanisms: increased intake, transcellular shift, or failure of excretion. Increased intake is typically a consequence of intravenous (IV) or oral potassium supplementation, or of packed red blood cell (pRBC) transfusion; the history of this patient is not supportive of either. Considering transcellular shifts and failure of excretion, important etiologies to consider in a patient of this age include certain medications, Addison's disease, metabolic acidosis (such as that cause by diabetic ketoacidosis), rhabdomyolysis, tumor lysis syndrome (TLS), and acute or chronic renal failure. Although this patient received corticosteroid therapy recently, these typically cause hypokalemia; while not mentioned in the history, he might have also used an inhaled beta-2-agonist at some point - these agents also tend to lower potassium levels. Rhabdomyolysis in this age group is typically a consequence of trauma or burns, and is somewhat unlikely in their absence. There are no clinical findings suggestive of Addison's disease (such as hypotension or hyperpigmentation); nor is hyponatremia (a common accompaniment of the disease) present. This makes this diagnosis less likely, although it cannot be completely ruled out. In addition, there are no signs or symptoms suspicious of malignancy (which might cause TLS), nor are there stigmata suggestive of chronic renal failure; this does not exclude these possibilities though. While the normal capillary blood glucose value makes diabetic ketoacidosis unlikely, the possibility of an alternate cause of metabolic acidosis cannot be ruled out either. As there is no clear clinical diagnosis, the next step should be targeted investigations. Thus, the normal renal function tests definitively exclude renal failure; the unremarkable arterial blood gas assay and creatinine phosphokinase (CPK) level exclude metabolic acidosis and rhabdomyolysis respectively. However, estimation of the serum calcium, phosphate, and uric acid levels proves to be fruitful by demonstrating the presence of hypocalcemia, hyperphosphatemia and hyperuricemia; note that this is sufficient to diagnose the presence of TLS. TLS is a life-threatening oncologic emergency; he requires urgent IV fluid therapy in order to maintain hydration and preserve renal function. Simultaneously, therapy with the potent uricolytic agent Rasburicase should be commenced to treat the hyperuricemia. A couple of questions arise: if this is indeed TLS, what is the underlying malignancy? And how did the TLS come about? While these questions can only be answered by further investigation, it is possible to guess at an answer by noting the recent history of oral corticosteroid therapy, and appreciating the fact that hematological malignancies such as lymphoma and acute lymphoblastic leukemia (ALL) are the commonest cancers in this age group. It is quite possible that this child has an underlying high-grade lymphoma or leukemia, on which the corticosteroids acted as a chemotherapeutic agent, causing cell lysis (and thus TLS). And in fact, further investigation of this patient eventually revealed the presence of a high-grade, primary mediastinal T-cell lymphoma.
Tumor Lysis Syndrome (TLS) is a life-threatening metabolic disorder which occurs when tumor cells undergo rapid decomposition spontaneously, or in response to cytoreductive therapy. The condition is most commonly encountered in patients with rapidly proliferating hematologic malignancies such as Burkitt lymphoma, large T-cell lymphoma, and acute lymphocytic leukemia (ALL); however, it can occur with any cancer. Note also that virtually any type of oncologic treatment can cause TLS, including systemic chemotherapy, intrathecal methotrexate, glucocorticoids, biological agents (such as rituximab), ionizing radiation, and tamoxifen. In addition, patient factors such as dehydration and renal failure can make the clearance of intracellular metabolites more difficult, thus increasing the risk of tumor lysis. In TLS, the rapid release of intracellular contents results in a classic constellation of biochemical abnormalities: hyperkalemia, hyperuricemia, hyperphosphatemia and secondary hypocalcemia. Most of the potassium in the body is stored in the intracellular compartment; rapid influx into the extracellular compartment can result in hyperkalemia, cardiac arrhythmias, and even sudden death. The nucleic acids released are broken down into purines, which in turn are metabolized into uric acid. The resulting hyperuricemia may overwhelm the renal excretory mechanisms and result in deposition of uric acid crystals in the renal tubules; this process is facilitated by an acidic urine environment. Hyperphosphatemia results from massive release of intracellular phosphate. This can lead to secondary hypocalcemia and deposition of calcium phosphate crystals in the kidney. Secondary hypocalcemia can also be symptomatic, with muscular, neurologic, and cardiovascular manifestations. Note that the acute kidney injury (AKI) caused by the deposition of calcium phosphate and urate crystals can be compounded further by a state of low urine flow in patients with volume depletion. The signs and symptoms of TLS are highly variable and may be due to one, several, or all of the abovementioned metabolic abnormalities. In practice, the most common symptoms are gastrointestinal complaints such as nausea, vomiting, diarrhea, and anorexia. Hyperuricemia often causes lethargy, hematuria, flank or back pain, fluid overload/edema, hypertension, signs of obstructive uropathy, or renal failure. Hyperkalemia can lead to muscular symptoms such as muscle weakness or paresthesia and cardiac abnormalities such as cardiac arrhythmias. Hyperphosphatemia and hypocalcemia may present clinically with neuromuscular, cardiac, and renal symptoms, including muscle cramps, tetany, seizures, cardiac arrhythmias, and renal failure. Note that TLS secondary to cytoreductive therapy usually presents within the first 72 hours of initiation of treatment. TLS is diagnosed via the Cairo and Bishop criteria; these divide the disease into 'Laboratory' TLS, and 'Clinical' TLS. Laboratory TLS: - Uric acid ≥ 8 mg/dL or 25% increase from baseline - Potassium ≥ 6 mEq/L or 25% increase from baseline - Phosphorus ≥ 6.5 mg/dL (children) or ≥ 4.5 mg/dL (adults) or 25% increase from baseline - Calcium ≤ 7 mg/dL or 25% decrease from baseline The diagnosis of 'Laboratory' TLS requires at least two positive criteria for three days before treatment or up to seven days after treatment. Clinical TLS: - Serum creatinine ≥ 1.5× the upper limit of the age-adjusted normal range - Cardiac arrhythmia or sudden death - Seizure The diagnosis of 'Clinical' TLS requires one clinical criterion, in addition to at least two laboratory criteria. TLS is an oncologic emergency; urgent action is essential to prevent acute kidney injury (AKI), and to reverse the existing electrolyte and metabolic abnormalities. Adequate hydration is a cornerstone of therapy, aiming to maintain renal function and promote metabolite excretion. In addition, any nephrotoxic agents or medications that may exacerbate the underlying fluid/electrolyte imbalance should be discontinued promptly, if at all possible. Treatment of the hyperuricemia is another key aspect of the management; drugs used include allopurinol, uricozyme, and rasburicase. Allopurinol prevents uric acid formation by inhibiting the enzyme xanthine oxidase; however, this does not affect the elimination of preformed uric acid, while it also causes an increase in the uric acid precursors xanthine and hypoxanthine, which themselves are poorly soluble. Rasburicase is a recombinant, highly purified form of urate oxidase which is highly effective for the management of hyperuricemia; it is the preferred therapeutic agent in the setting of TLS. It should be appreciated that rasburicase will continue to degrade uric acid in blood samples, even after withdrawal. Thus, all blood samples should be kept on ice immediately after being drawn, and assayed for uric acid levels within a period of 4 hours. While urinary alkalinization might seem to be an attractive method of preventing urate nephropathy (as an alkaline environment increases the solubility of uric acid), it should be noted that this simultaneously decreases the solubility of calcium phosphate - and hyperphosphatemia is more difficult to correct than hyperuricemia. The treatment of hyperphosphatemia includes hydration and forced diuresis, administration of oral phosphate binders such as aluminum hydroxide, and in severe cases, hemodialysis. Hyperkalemia should be treated with hydration and administration of loop diuretics and oral potassium binders such as sodium polystyrene sulfonate; in an emergency situation, nebulization with a beta-2-agonist, or a rapid acting insulin combined with a glucose infusion may be used to rapidly shift potassium into the intracellular compartment. Despite optimal care, severe AKI will develop in some patients, necessitating renal replacement therapy. Given the dire sequelae of TLS, prophylactic measures should be undertaken prior to administering cytoreductive therapy to at-risk patients. This includes vigorous hydration and maintenance of a good urine output, along with monitoring of ﬂuid balance, weight and serum electrolytes. Allopurinol may also be administered prophylactically, to prevent hyperuricemia.