Lactic acidosis in a patient with cancer.

Lactic acidosis is commonly associated with tissue hypoperfusion and gives rise to concern regarding hypoxia or underlying hypotension. In the cancer patient, especially one undergoing chemotherapy, there is always concern for sepsis; however, in the otherwise clincially stable patient with cancer, type B lactic acidosis can also be related to their underlying malignancy. It is considered a haematological emergency given its high mortality rate. However, despite the urgency to treat type B lactic acidosis in these circumstances, treatment options beyond treatment of the malignancy are limited, and its presence portends a poor prognosis. This case highlights our current understanding of type B lactic acidosis and an approach to lactic acidosis evaluation in the cancer patient.

Severe lactic acidosis during tenofovir disoproxil fumarate and cobicistat combination for HIV patient.

Lactic acidosis is a rare but serious side effect in individuals receiving nucleoside reverse transcriptase inhibitors. An underweight woman with HIV was admitted to our hospital because of nausea and diffuse myalgia. Her antiretroviral regimen had been changed to tenofovir disoproxil fumarate (TDF)/emtricitabine and darunavir/cobicistat 3 months prior, after which her renal function had gradually declined. After admission, she was diagnosed with lactic acidosis, and a liver biopsy suggested mitochondrial damage. Her plasma tenofovir levels were elevated at the onset of lactic acidosis. We hypothesise that the patient's low body weight, combined with the addition of cobicistat, induced renal dysfunction and led to elevated plasma tenofovir concentrations, resulting in mitochondrial damage and lactic acidosis. Careful monitoring of renal function and lactic acidosis is required during use of TDF-containing regimens for underweight HIV patients, particularly when combined with cobicistat.

Lactic acidosis after allogeneic haematopoietic stem cell transplantation potentially related to letermovir.

A 53-year-old woman with a history of acute myeloid leukaemia received a second allogeneic haematopoietic stem cell transplant and was prescribed, among other medications, acyclovir and letermovir (480-mg daily oral dose) for prophylaxis of, respectively, herpes simplex and cytomegalovirus infection. The patient was admitted in the intensive care unit for dyspnoea and oliguria. Laboratory investigations revealed acute kidney injury but also a severe and progressive lactic acidosis. Liver function tests were within normal range. The combination of lactic acidosis, hypoglycaemia and acylcarnitine profile in plasma raised the suspicion of mitochondrial toxicity. Letermovir therapy was interrupted, and determination of plasma letermovir pharmacokinetics revealed a prolonged terminal half-life (38.7 h) that was not significantly influenced by continuous venovenous haemofiltration. Exploration for genetic polymorphisms revealed that the patient was SLCO1B1*5/*15 (c.521T>C homozygous carrier and c.388A>G heterozygous carrier) with a predicted nonfunctional organic anion transporting polypeptide 1B1 protein. The relationship between letermovir accumulation and development of lactic acidosis requires further observations.

Metformin as an emerging concern in wastewater: Occurrence, analysis and treatment methods.

Metformin is a wonder drug used as an anti-hypoglycemic medication; it is also used as a cancer suppression medicament. Metformin is a first line of drug choice used by doctors for patients with type 2 diabetes. It is used worldwide where the drug's application varies from an anti-hypoglycemic medication to cancer oppression and as a weight loss treatment drug. Due to its wide range of usage, metformin and its byproducts are found in waste water and receiving aquatic environment. This leads to the accumulation of metformin in living beings and the environment where excess concentration levels can lead to ailments such as lactic acidosis or vitamin B12 deficiency. This drug could become of future water treatment concerns with its tons of production per year and vast usage. As a result of continuous occurrence of metformin has demanded the need of implementing and adopting different strategies to save the aquatic systems and the exposure to metformin. This review discuss the various methods for the elimination of metformin from wastewater. Along with that, the properties, occurrence, and health and environmental impacts of metformin are addressed. The different analytical methods for the detection of metformin are also explained. The main findings are discussed with respect to the management of metformin as an emerging contaminants and the major recommendations are discussed to understand the major research gaps.

Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming.

Lactic acidosis, the extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues. Macrophages are able to differentiate from monocytes under such acidotic conditions, and remain active in order to resolve the underlying injury. Here we show that, in lactic acidosis, human monocytes differentiating into macrophages are characterized by depolarized mitochondria, transient reduction of mitochondrial mass due to mitophagy, and a significant decrease in nutrient absorption. These metabolic changes, resembling pseudostarvation, result from the low extracellular pH rather than from the lactosis component, and render these cells dependent on autophagy for survival. Meanwhile, acetoacetate, a natural metabolite produced by the liver, is utilized by monocytes/macrophages as an alternative fuel to mitigate lactic acidosis-induced pseudostarvation, as evidenced by retained mitochondrial integrity and function, retained nutrient uptake, and survival without the need of autophagy. Our results thus show that acetoacetate may increase tissue tolerance to sustained lactic acidosis.

Intravascular lymphoma presenting with hypoxaemia, platypnoea and lactic acidosis.

Intravascular large B-cell lymphoma (IVLBCL) is an aggressive and rare type of diffuse extranodal B-cell lymphoma. Diagnosis and treatment are challenging and clinical presentation is variable. Physicians should be aware of this rare but life-threatening lymphoma without adenopathy and treatment should be promptly started. We describe the case of a 70-year-old woman who presented with general malaise, acute dyspnoea, platypnoea and lactic acidosis. Echocardiography revealed an extracardiac shunt, the cause of her orthodeoxia. The patient developed rapid liver failure and underwent liver biopsy. Anatomopathological findings suggested IVLBCL, non-germinal center type. She achieved complete remission after rituximab, cyclophosphamide, doxorubicin, vincristine, methylprednisolone chemotherapy but relapsed 1 year after initial presentation with multiple organ involvement. The patient's relapsed disease was treated with rituximab, iphosphamide, carboplatin, etoposide and she is still in complete remission 2 years later.

Malignancy-induced lactic acidosis in adult lymphoma.

Malignancy-induced lactic acidosis (MILA), a rare paraneoplastic phenomenon, is mostly described with hematologic malignancies (lymphomas and leukemias) but has also been reported with solid tumors. It is a subset of type B lactic acidosis being mediated without evidence of tissue hypoperfusion. Lymphoma-induced lactic acidosis is often considered an oncologic emergency and is associated with an increased risk of mortality and poor prognosis. It has a complex pathophysiology centered in the "Warburg effect," i.e., the programming of cancer cells to depend on aerobic glycolysis for promotion of their proliferation and anabolic growth. The treatment of lymphoma-induced lactic acidosis is focused on prompt administration of chemotherapy. The role of alkali therapy in this setting is controversial and has limited proven benefit with a potential for worsening the lactic acidosis. If alkali therapy is used in the presence of severe acidemia to optimize cardiovascular status, it should be administered judiciously.

Lactic acidosis induces resistance to the pan-Akt inhibitor uprosertib in colon cancer cells.

BACKGROUND: Akt signalling regulates glycolysis and drives the Warburg effect in cancer, thus decreased glucose utilisation is a pharmacodynamic marker of Akt inhibition. However, cancer cells can utilise alternative nutrients to glucose for energy such as lactate, which is often elevated in tumours together with increased acidity. We therefore hypothesised that lactic acidosis may confer resistance to Akt inhibition. METHODS: The effect of the pan-Akt inhibitor uprosertib (GSK2141795), on HCT116 and LS174T colon cancer cells was evaluated in the presence and absence of lactic acid in vitro. Expression of downstream Akt signalling proteins was determined using a phosphokinase array and immunoblotting. Metabolism was assessed using 1H nuclear magnetic resonance spectroscopy, stable isotope labelling and gas chromatography-mass spectrometry. RESULTS: Lactic acid-induced resistance to uprosertib was characterised by increased cell survival and reduced apoptosis. Uprosertib treatment reduced Akt signalling and glucose uptake irrespective of lactic acid supplementation. However, incorporation of lactate carbon and enhanced respiration was maintained in the presence of uprosertib and lactic acid. Inhibiting lactate transport or oxidative phosphorylation was sufficient to potentiate apoptosis in the presence of uprosertib. CONCLUSIONS: Lactic acidosis confers resistance to uprosertib, which can be reversed by inhibiting lactate transport or oxidative metabolism.

Lessons of the month 1: Salbutamol induced lactic acidosis: clinically recognised but often forgotten.

We present the case of an 83-year-old woman, with known asthma, admitted with increasing dyspnoea, wheeze and a productive cough. In addition to maintenance inhaled therapy, the patient was also on long-term mirtazapine and furosemide. Following acute treatment with nebulised salbutamol she became increasingly dyspnoeic and developed a metabolic acidosis with a significantly raised blood lactate level. After cessation of ß2-adrenergic medication, the patient's clinical condition improved with resolution of her lactic acidosis; salbutamol induced lactic acidosis was diagnosed. This clinical scenario is common but not well described. Here we discuss the mechanisms, investigation and management of raised serum lactate and lactic acidosis in the context of acute asthma and the possible interactions of polypharmacy and comorbidities in the acute medical setting.

A Case of Renal Involvement in B Lymphoblastic Lymphoma Leukemia.

BACKGROUND: Renal involvement is rare in B lymphoblastic lymphoma (B-LBL). The authors describe a rare case of renal involvement in a 21-year-old male patient with B lymphoblastic lymphoma leukemia, presenting with severe lactic acidosis. METHODS: Hematologic investigation, bone marrow aspirate and biopsy, cytogenetic analysis and renal biopsy were performed. RESULTS: The patient achieved complete hematological remission (CHR) after induction therapy with the regimen of VDCP and received consolidation chemotherapy regularly. He remained CHR until now. CONCLUSIONS: Renal biopsy, bone marrow aspirate, and biopsy are important to confirm a correct diagnosis. Renal involvement in B-LBL as a prognostic factor needs further studies.

Vitamin B1 for type B metabolic acidosis: An underrecognized approach.

Lactic acidosis is a life-threatening and rather common complication and reason for consultation to the nephrologist. The cause for this condition is usually thought to be secondary to hypoperfusion and ischemia collectively. However, many other rare causes have been described, yet there is little awareness of these, consequently delaying optimal care. We present a multifactorial case of lactic acidosis due to thiamine deficiency, liver disease, and lymphoma; all underrecognized causes of Type B lactic acidosis.

Type B lactic acidosis, an uncommon paraneoplastic syndrome.

A 67-year-old male presented with anasarca and persistent non-pruritic rash of lower extremities. Physical examination was positive for subcutaneous edema with a non-blanching rash of abdomen and lower extremities. Labs showed leukocytosis, lymphocytosis, anemia and thrombocytopenia. He also had acute kidney injury and high anion gap (AG) metabolic acidosis with elevated lactic acid (11.3 mg/dL). Computerized tomography (CT) of abdomen and pelvis showed hepatosplenomegaly, ascites and abdominal lymphadenopathy. Peripheral blood (PB) smear showed blastiod appearing lymphocytes. He was started on bicarbonate infusion due to persistent lactic acidosis (LA), however showed no significant improvement. He was started on IV dexamethasone on 3rd day of hospitalization based on preliminary result of peripheral picture which led to some improvement in LA. Following the confirmation of mantle cell lymphoma (MCL) on bone marrow (BM) biopsy and immunophenotyping, the patient started receiving VR-CAP regimen (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) which led to significant improvement in LA and leukocytosis. After discharge, he received further chemotherapy with resolution of the LA and normalization of blood counts. Restaging tests confirmed a complete remission with resolution of the skin rash, resolution of the pathological lymphadenopathy and hepatosplenomegaly on imaging, and absence of lymphoma on a repeat BM biopsy.

In vivo evaluation of tumour acidosis for assessing the early metabolic response and onset of resistance to dichloroacetate by using magnetic resonance pH imaging.

Dichloroacetate (DCA) can reverse the glycolytic phenotype that is responsible of increased lactate production and extracellular pH acidification in cancer cells. Magnetic resonance imaging-chemical exchange saturation transfer (MRI-CEST) pH mapping is a novel non-invasive imaging approach that can measure in vivo extracellular tumour pH. We examined whether MRI-CEST pH mapping can monitor in vivo changes in tumour acidosis for assessing treatment response to DCA. Cell viability and extracellular pH were assessed in TS/A breast cancer cells treated with 1-10 mM DCA for 24 h in normoxia or hypoxia (1% O2) conditions. Extracellular tumour pH values were measured in vivo by MRI-CEST pH mapping of TS/A tumour-bearing mice before, three days and fifteen days after DCA or saline treatment. Reduced extracellular acidification and vitality were observed in DCA-treated TS/A cells. Tumour-bearing mice showed a marked and significant increase of tumour extracellular pH at 3 days post-DCA treatment, reflecting DCA-induced glycolysis inhibition, as confirmed by reduced lactate production. After 15 days of DCA treatment, the onset of resistance to DCA was observed, with recover of tumour extracellular acidification and lactate levels that returned to baseline values. A significant correlation was observed between tumour extracellular pH values and lactate levels (r= -0.97, P<0.05). These results suggest that MRI-CEST pH imaging is a promising tool to monitor the early response and efficacy of cancer metabolic targeting drugs.

Lifetime exercise intolerance with lactic acidosis as key manifestation of novel compound heterozygous ACAD9 mutations causing complex I deficiency.

We report a 36-year-old female having lifetime exercise intolerance and lactic acidosis with nausea associated with novel compound heterozygous Acyl-CoA dehydrogenase 9 gene (ACAD9) mutations (p.Ala390Thr and p.Arg518Cys). ACAD9 is an assembly factor for the mitochondrial respiratory chain complex I. ACAD9 mutations are recognized as frequent causes of complex I deficiency. Our patient presented with exercise intolerance, rapid fatigue, and nausea since early childhood. Mild physical workload provoked the occurrence of nausea and vomiting repeatedly. Her neurological examination, laboratory findings and muscle biopsy demonstrated no abnormalities. A bicycle spiroergometry provoked significant lactic acidosis during and following exercise pointing towards a mitochondrial disorder. Subsequently, the analysis of respiratory chain enzyme activities in muscle revealed severe isolated complex I deficiency. Candidate gene sequencing revealed two novel heterozygous ACAD9 mutations. This patient report expands the mutational and phenotypic spectrum of diseases associated with mutations in ACAD9.

A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis.

Background: Previous works suggested that neutralizing intratumoral lactic acidosis combined with glucose deprivation may deliver an effective approach to control tumor. We did a pilot clinical investigation, including a nonrandomized (57 patients with large HCC) and a randomized controlled (20 patients with large HCC) study. Methods: The patients were treated with transarterial chemoembolization (TACE) with or without bicarbonate local infusion into tumor. Results: In the nonrandomized controlled study, geometric mean of viable tumor residues (VTR) in TACE with bicarbonate was 6.4-fold lower than that in TACE without bicarbonate (7.1% [95% CI: 4.6%­10.9%] vs 45.6% [28.9%­72.0%]; p<0.0001). This difference was recapitulated by a subsequent randomized controlled study. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may bring survival benefit. Conclusions: Bicarbonate markedly enhances the anticancer activity of TACE. Funding: Funded by National Natural Science Foundation of China. Clinical trial number: ChiCTR-IOR-14005319.

Surgery is the main treatment for liver cancer, but the most common liver cancer ­ called hepatocellular carcinoma ­ can sometimes become too large to remove safely. An alternative option to kill the tumor is to block its blood supply via a process called embolization. This procedure deprives the tumor cells of oxygen and nutrients such as glucose. However, embolization also prevents a chemical called lactic acid ­ which is commonly found around tumors ­ from being removed. Lactic acid actually helps to protect cancer cells and also aids the growth of new blood vessels, and so the "trapped" lactic acid may reduce the anticancer activity of embolization. Previous works suggested that neutralizing the acidic environment in a tumor while depriving it of glucose via embolization could become a new treatment option for cancer patients. Chao et al. now report a small clinical trial that tested this idea and involved patients with large hepatocellular carcinomas. First, a group of thirty patients received the embolization treatment together with an injection of bicarbonate ­ a basic compound used to neutralize the lactic acid ­ that was delivered directly to the tumor. The neutralization killed these large tumors more effectively than what is typically seen in patients who just undergo embolization Chao et al. then recruited another twenty patients and randomly assigned them to receive either just the embolization or the embolization with bicarbonate treatment. This randomized trial showed that the tumors died more and patients survived for longer if they received the bicarbonate together with the embolization treatment compared to those patients that were only embolized. In fact, four patients initially assigned to, and treated in, the embolization-only group subsequently asked to cross over to, and indeed received, the bicarbonate treatment as well. These data indicate that this bicarbonate therapy may indeed be effective for patients with large tumors that are not amenable to surgery. In future, larger clinical trials will need to be carried out to verify these initial findings.

Type B Lactic Acidosis Associated With Venlafaxine Overdose.

Lactic acidosis that is not secondary to tissue hypoperfusion or hypoxemia (type B lactic acidosis) is a rare but potentially fatal condition that has been associated with drugs like metformin, linezolid, and nucleoside reverse-transcriptase inhibitors in patients with HIV. We report the first case of type B lactic acidosis caused by overdose of the serotonin-norepinephrine reuptake inhibitor, venlafaxine. A 55-year-old man with no significant medical history was brought to the emergency department after intentional ingestion of around 80 capsules of venlafaxine (a total dose of over 6000 mg) in an attempt to commit suicide. Complete blood count and comprehensive metabolic panel were unremarkable except for a bicarbonate level of 13 mEq/L and an anion gap of 22 mEq/L. An arterial blood gas revealed a pH of 7.39, partial pressure of CO2 of 19 mm Hg, calculated bicarbonate of 11.5 mEq/L, and a lactate level of 8.6 mmol/L. The patient was started on aggressive intravenous hydration with normal saline along with oral activated charcoal with sorbitol. Repeat laboratory work after 4 hours showed an improvement in anion gap (15 mEq/L) and serum lactate (5.6 mmol/L). The patient remained stable throughout the hospital stay and lactic acidosis resolved in 24 hours. In the absence of hypotension, hypoxemia, kidney or liver dysfunction, myopathy, malignancy, or use of other medications, venlafaxine was the most likely cause of lactic acidosis in our case. Rapid improvement of acidosis was probably related to clearance of the drug.

Acute thiamine deficiency and refeeding syndrome: Similar findings but different pathogenesis.

OBJECTIVE: Refeeding syndrome can occur in several contexts of relative malnutrition in which an overaggressive nutritional support is started. The consequences are life threatening with multiorgan impairment, and severe electrolyte imbalances. During refeeding, glucose-involved insulin secretion causes abrupt reverse of lipolysis and a switch from catabolism to anabolism. This creates a sudden cellular demand for electrolytes (phosphate, potassium, and magnesium) necessary for synthesis of adenosine triphosphate, glucose transport, and other synthesis reactions, resulting in decreased serum levels. Laboratory findings and multiorgan impairment similar to refeeding syndrome also are observed in acute thiamine deficiency. The aim of this study was to determine whether thiamine deficiency was responsible for the electrolyte imbalance caused by tubular electrolyte losses. METHODS: We describe two patients with leukemia who developed acute thiamine deficiency with an electrolyte pattern suggestive of refeeding syndrome, severe lactic acidosis, and evidence of proximal renal tubular dysfunction. RESULTS: A single thiamine administration led to rapid resolution of the tubular dysfunction and normalization of acidosis and electrolyte imbalance. This demonstrated that thiamine deficiency was responsible for the electrolyte imbalance, caused by tubular electrolyte losses. CONCLUSIONS: Our study indicates that, despite sharing many laboratory similarities, refeeding syndrome and acute thiamine deficiency should be viewed as separate entities in which the electrolyte abnormalities reported in cases of refeeding syndrome with thiamine deficiency and refractory lactic acidosis may be due to renal tubular losses instead of a shifting from extracellular to intracellular compartments. In oncologic and malnourished patients, individuals at particular risk for developing refeeding syndrome, in the presence of these biochemical abnormalities, acute thiamine deficiency should be suspected and treated because it promptly responds to thiamine administration.

A rare metabolic complication of acute lymphoblastic leukemia in childhood: lactic acidosis.

A 13-year-old boy presented with nausea, fatigue, weight loss, and bone pain for two months. Complete blood count and serum renal and liver function tests were all normal. Blood gas analysis revealed severe metabolic acidosis with high anion gap. Lactate level was 61.2 mmol/L. Abdominal ultrasonography yielded bilateral nephromegaly and hepatomegaly with increased echogenicity. Peripheral blood smear revealed 2% blasts. Bone marrow aspiration showed 'Common ALL Antigen'-negative acute lymphoblastic leukemia by flow cytometric analysis. Metabolic acidosis dissolved as soon as chemotherapy was begun. Lactic acidosis at the presentation of acute lymphoblastic leukemia--especially with low tumor burden--is a very rare and almost always fatal complication. Our patient is still alive and in remission, which is a point of interest in this child.