Acute Liver Failure as the Leading Manifestation of Spontaneous Tumour Lysis Syndrome in a Patient with NonHodgkin Lymphoma: Do Current Diagnostic Criteria of Tumour Lysis Syndrome Need Re-Evaluation?

Tumour lysis syndrome (TLS) is a group of pathophysiological processes caused by rapid degradation of tumour cells with subsequent release of intracellular contents into the extracellular space. It is characterized by the development of systemic metabolic disturbances with or without clinical manifestations. The process usually occurs in highly proliferative, large tumours after induction of cytotoxic therapy. Rarely, however, spontaneous TLS can develop, as well as signs of multiorgan failure triggered by an excessive metabolic load and sterile inflammation. The combination of the aforementioned is thus quite unique. Here, we present a 63-year-old male in which spontaneous TLS was accompanied with acute liver failure and delineated underlying nonHodgkin lymphoma. Initial laboratory findings included hyperkalaemia, hyperphosphataemia, hypocalcaemia, uraemia, and increased creatinine levels indicating the onset of TLS with acute kidney injury. Moreover, the patient showed signs of jaundice, coagulopathy, and hepatic encephalopathy. Development of TLS with multiorgan failure prompted rapid initiation of critical care management, including vigorous intravenous fluid therapy, allopurinol treatment, high flow continuous venovenous haemodiafiltration, and commencement of chemotherapy. The case highlights the possibility of TLS as a differential diagnosis in patients presenting with multiorgan failure and the importance of early detection of this potentially challenging and fatal diagnosis.


Introduction
Tumour lysis syndrome (TLS) is a group of pathophysiological processes that occur when tumour cells start to rapidly degrade [1][2][3]. The subsequent release of intracellular contents into the extracellular space and blood typically leads to systemic metabolic disturbances with or without clinical manifestations [1][2][3]. The syndrome usually develops in patients with highly proliferative tumours, a relatively large tumour burden, and a high sensitivity to cytotoxic therapy, such as haematologic malignancies [1][2][3][4]. Although rare, spontaneous TLS can occur before the initiation of cytotoxic therapy and accounts for about 1% of all cases of TLS [5][6][7].
On top of mentioned metabolic products, damaged or stressed tumour cells can release a wide range of mediators called damage-associated molecular patterns (DAMPs), which trigger sterile inflammation [12][13][14][15]. As with other metabolic contents, DAMPs from tumour cells can be released spontaneously or during chemotherapy [12,16]. This may lead to toll-like receptor-mediated inflammasome activation, neutrophil activation, and release of reactive oxygen species, inflammatory mediators, and proteolytic enzymes with subsequent development of systemic inflammatory response syndrome (SIRS) and multiorgan failure [12,14,15].
Here, we present a 63-year-old, previously healthy, male in which acute liver failure was the leading manifestation of spontaneous TLS and delineated underlying nonHodgkin lymphoma (NHL).

Case Presentation
A 63-year-old white male presented at the Emergency Department (ED) with abdominal pain and nausea. Detailed medical history revealed that the patient had suffered from loss of appetite, upper abdominal pain, and fever for two weeks. Apart from mentioned, the patient was previously in good general health and without any chronic therapy.
Initial physical examination at the ED showed an enlarged liver and jaundice. Laboratory tests indicated leucocytosis, increased creatinine and urea levels, elevated liver enzymes and hyperbilirubinaemia with cholestatic pattern, and impaired . Both conjugated and nonconjugated bilirubin showed some initial improvement. However, they remained high throughout the course of ICU-treatment (c). After initial improvement, the liver enzymes showed progressively high cholestatic pattern (c, d). Black arrows mark values above laboratory reference range ((a)-(d)).       contractility and valvular function, together with collapsible vena cava inferior and no pericardial effusion. Vigorous treatment with balanced intravenous fluid supplementation was commenced, followed by the initiation of high flow continuous venovenous haemodiafiltration with albumin replacement, broad-spectrum antibiotics and allopurinol therapy. Rasburicase would have been a preferential therapy over allopurinol due to its higher efficiency and the fact that it rapidly reduces existing hyperuricaemia. Unfortunately, in our hospital it was not available at that time. Acid-base and electrolyte disturbances, specifically hypocalcaemia and hyperkalaemia, were corrected in accordance with regular laboratory assessments and with the help of renal replacement therapy (RRT). When the biopsy results arrived the next day, the induction therapy with methylprednisolone and cyclophosphamide was started (ICU-day 2). In particular, the specimens contained numerous mitoses and apoptotic cells, together with abundant necrotic areas and plain cellular nuclei. The tumour cells had centroblast/immunoblast morphology, immunophenotype that corresponded to peripheral lymphocytes B NHL (Diffuse Large Cell Lymphoma B, DLBCL), double BCL-2/C-MYC protein expression (CD20+/BCL-2+/BCL-6+/MUM-1+/ CD10−/CD5−/CD3−) and C-MYC positive in 50% of cells. The constellation of findings consisting of hyperkalaemia, hypocalcaemia, and hyperphosphataemia on ICU-day 1, together with acute kidney injury and abovementioned biopsy findings, lead to the confirmation of previously suspected TLS.
Provided measures and therapy lead to improvement of patient's condition and initiation of triple-drug cytostatic therapy on ICU-day 3. In the following days, patient's laboratory signs showed gradual improvement in electrolyte, urate, and renal function tests, as well as liver enzymes. The patient was weaned from RRT on the ICU-day 5, with subsequent spontaneous diuresis augmented with fractional administration of furosemide and measuring >1 ml/kg/h. On ICU-day 8, the patient was fully awake, cooperative, and weaned from the ventilator. He was transferred to the High Dependency Unit of the Haematology Department on ICU-day 10 fully awake, respiratory and hemodynamically stable with normalization of potassium, calcium, phosphate, ammonium, and urea levels ( Table 1, ICU day 10). However, although both conjugated and nonconjugated bilirubin showed some initial improvement, they remained high throughout the course of ICU-treatment and the leading manifestation of the underlying DLBCL (Table 1, time point: ICU-day 3-9). Following ICU, the patient continued haematology treatment and was discharged from the hospital 55 days after the admission.

Discussion
TLS is potentially lethal oncologic emergency [1,3,8,11]. However, it usually occurs in patients with known underlying disease and after the initiation of cytotoxic therapy [1,[8][9][10]. In the case presented here, the patient did not have a diagnosed malignancy at the presentation. On contrary, it was a specific laboratory pattern consisting of hyperkalaemia, hypocalcaemia, upper limit values of phosphates, and high LDH levels together with a retroperitoneal mass of undetermined characteristics, blood coagulation tests ( Figure 1 and Table 1, time point: pre-ICU). Radiology investigation included chest X-ray (CXR) and abdominal ultrasound, followed by computed tomography of thorax and abdomen. CXR was within normal limits and excluded acute inflammation or infiltration of the lungs. Abdominal ultrasound showed an enlarged spleen and liver, the latter without focal lesions or dilation of intra-or extrahepatic bile ducts and gall bladder of normal size and wall thickness. Moreover, a retroperitoneal mass of undetermined characteristics was visualized in close proximity to the left kidney, measuring 7 cm in diameter. In the right kidney, a parenchymal cyst was detected, measuring 4.5 cm in diameter. The remainder of the ultrasound examination was within normal limits. Subsequent computed tomography (CT) enhanced with orally administered diatriazoate meglumine and diatrizoate sodium solution revealed a retroperitoneal mass with complete infiltration of both iliopsoas muscles and posteromedial portions of both kidneys, separate mass in the ventral portion of the left kidney and enlarged liver and spleen ( Figure 2). No signs of urinary tract dilation were visible. Liver measured 25 cm in craniocaudal diameter and, despite cholestatic pattern in laboratory investigations, showed no signs of obstruction or dilatation in the biliary tract. Spleen measured 15.3 cm and had an infarction zone. Simultaneously with these diagnostic imaging methods, a needle biopsy of the retroperitoneal mass was made, after the correction of coagulopathy with 20 ml/kg of fresh frozen plasma.
After the procedure, clinical state of the patient progressively deteriorated within the next few hours with both clinical and laboratory signs of acute liver failure and acute kidney injury, raising suspicion of TLS. Physical examination using ABCDE approach showed that the patient had patent airway, respiratory rate 22 breaths/minute, SpO 2 92-95% with supplemental oxygen (2 L via nasal cannula), normal finding over the lungs on auscultation and percussion, blood pressure of 150/75 mmHg, heart rate of 95/min that was palpable over central and peripheral arteries, capillary refill time <2 seconds, skin warm and sweaty, Glasgow Coma Score measured 13 (E3, V4, M6) with progressively worsening agitation, pupils were equally sized and reactive to light, no lateralisation were noticed, body temperature was 36.9°C, abdomen was above the level of the thorax with palpable liver, painful on deep palpation and intraabdominal pressure measuring 13 mmHg. Laboratory tests at that stage showed profound hyperbilirubinaemia with elevated liver enzymes, hyperammonaemia and coagulopathy (prolonged APTT and PT/INR), together with thrombocytopaenia, increased lactate dehydrogenase (LDH) levels, hyperkalaemia, hyperphosphataemia, hypocalcaemia, and uraemia (Table 1, time point: ICU-day 1), and the patient was admitted to intensive care unit (ICU) with SAPS II score of 52 and predicted in-hospital mortality of 50.7%. Due to the development of severe agitation and hepatic encephalopathy, followed by decreased level of consciousness and inability to properly maintain patent airway, the patient was sedated, an endotracheal tube was placed to protect the airway and lung protective ventilation was started. No cardiac dysrhythmias were recorded on the initial 12-channel ECG or during continuous monitoring via the 3-channel ECG. Orientational echocardiography was made and showed heart of normal size, account patient's rapid deterioration from full health, laboratory findings, and histology results showing haematological malignancy with high proliferation grade, the diagnosis of TLS was made. In 2004, Cairo and Bishop proposed distinction of TLS depending on whether laboratory in previously healthy patient, which raised suspicion of spontaneous TLS. Symptomatic treatment of acute liver failure and acute kidney injury preceded the definitive diagnosis of DLBCL, after which induction, and then triple-drug cytostatic therapy was started when final diagnosis was made. Taken into the primary liver function in metabolic processes makes this organ potentially highly susceptible to injury when faced with extreme metabolic load from damaged cells. Accordingly, we suggest routine investigation of liver function tests when TLS is suspected. Corroborating the fact that TLS criteria have the potential to be improved since too little attention has been focused on this potentially fatal diagnosis, we can conclude that our patient had SIRS and multiorgan failure due to the underlying haematologic malignancy. We acknowledge the fact that our patient's laboratory findings did not fully meet Cairo and Bishop's criteria for laboratory TLS. However, the patient had clear laboratory pattern consistent with TLS, pronounced SIRS and multiorgan failure. In the absence of other possible causes for this profoundly deranged state, it is reasonable to assume that the DLBCL was the underlying cause. Therefore, we believe that reports on TLS patients' clinical course and different organ involvement should be intensified in order to set new diagnostic guidelines, taking into account the patient's general condition, underlying disease, and course of clinical treatment. In that way, TLS as a life-threatening condition, that can be obscured by the clinical image of multiorgan failure, can be properly recognized.

Consent
The consent for publishing this case report, together with laboratory data and images, was obtained from both the patient and Institutional Review Board.