-
Cells Mar 2023Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the...
Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune cells). Adipose tissue also represents a crucial component of the TME which is receiving increasing attention due to its pro-tumoral activity, however, to date, it is not known whether it could be affected by the acidic TME. Now, emerging evidence from chronic inflammatory and fibrotic diseases underlines that adipocytes may give rise to pathogenic myofibroblast-like cells through the adipocyte-to-myofibroblast transition (AMT). Thus, our study aimed to investigate whether extracellular acidosis could affect the AMT process, sustaining the acquisition by adipocytes of a cancer-associated fibroblast (CAF)-like phenotype with a pro-tumoral activity. To this purpose, human subcutaneous adipose-derived stem cells committed to adipocytes (acADSCs) were cultured under basal (pH 7.4) or lactic acidic (pH 6.7, 10 mM lactate) conditions, and AMT was evaluated with quantitative PCR, immunoblotting, and immunofluorescence analyses. We observed that lactic acidosis significantly impaired the expression of adipocytic markers while inducing myofibroblastic, pro-fibrotic, and pro-inflammatory phenotypes in acADSCs, which are characteristic of AMT reprogramming. Interestingly, the conditioned medium of lactic acidosis-exposed acADSC cultures was able to induce myofibroblastic activation in normal fibroblasts and sustain the proliferation, migration, invasion, and therapy resistance of breast cancer cells in vitro. This study reveals a previously unrecognized relationship between lactic acidosis and the generation of a new CAF-like cell subpopulation from adipocytic precursor cells sustaining tumor malignancy.
Topics: Humans; Myofibroblasts; Cancer-Associated Fibroblasts; Acidosis, Lactic; Tumor Microenvironment; Endothelial Cells; Adipocytes; Neoplasms; Lactic Acid
PubMed: 36980280
DOI: 10.3390/cells12060939 -
Journal of Internal Medicine Feb 2004Metformin has been associated with the serious side-effect lactic acidosis. However, it remains unclear whether the use of metformin was a cause or a coincidence in... (Review)
Review
OBJECTIVE
Metformin has been associated with the serious side-effect lactic acidosis. However, it remains unclear whether the use of metformin was a cause or a coincidence in lactic acidosis.
DESIGN
A literature search of the Index Medicus (1959-66) and of the databases Embase, Medline, Medline Express (1966-99) was performed using the keywords metformin, biguanides and lactic acidosis. All articles of cases with metformin-induced lactic acidosis (MILA) were cross-referenced.
SUBJECTS
Cases were included for analysis if they met the following criteria: serum pH < or =7.35, lactate concentration > or =5 mmol L(-1).
INTERVENTION
A forum of six experts in intensive care medicine independently categorized the cases in MILA unlikely (score 0), possible MILA (score 1) or probable MILA (score 2).
MAIN OUTCOME MEASURES
Statistical analysis included the paired interobserver agreement (kappa) and multivariate regression analysis.
RESULTS
Of 80 reported cases, 33 were excluded because of insufficient quality. The forum scores of the remaining 47 cases were distributed normally with a mean score of 7 (range 2-10). The kappa-value was 0.041 (SD = 0.24, range -0.514, 0.427). Neither lactate concentration nor mortality correlated with serum metformin concentrations.
CONCLUSIONS
Given the low interobserver agreement and the lack of any relationship between metformin levels and outcome parameters, the concept that there is a simple, causal relationship between metformin use and lactic acidosis in diabetic patients has to be reconsidered.
Topics: Acidosis, Lactic; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Male; Medical Records; Metformin; Middle Aged; Regression Analysis; Risk Factors
PubMed: 14746555
DOI: 10.1046/j.1365-2796.2003.01271.x -
Pharmacology 2023Metformin-treated patients may experience severe hyperlactatemia or lactic acidosis (LA). LA often requires intensive-care-unit (ICU) treatment, and mortality rates are...
INTRODUCTION
Metformin-treated patients may experience severe hyperlactatemia or lactic acidosis (LA). LA often requires intensive-care-unit (ICU) treatment, and mortality rates are high. Here, we investigate the impact of renal dysfunction and renal replacement therapy (RRT) on the outcomes of critically ill patients with metformin-associated LA (MALA). Furthermore, we assessed associations between mortality and metformin dose, metformin plasma/serum concentrations, lactate level, and arterial pH. Finally, we investigated whether the recommended classification in MALA, metformin-unrelated LA, metformin-induced LA, and LA in metformin therapy appears useful in this regard.
METHODS
We performed a retrospective analysis based on a systematic PubMed search for publications on hyperlactatemia/LA in metformin-treated ICU patients from January 1995 to February 2020. Case-level data including demographics and clinical conditions were extracted, and logistic regression analyses were performed.
RESULTS
A total of 92 ICU patients were reported. Two of these patients had no comorbidities interfering with lactate metabolism. In the overall group, arterial pH, lactate levels, and metformin plasma/serum concentrations were similar in survivors versus non-survivors. Ingested daily metformin doses and plasma/serum creatinine levels were significantly higher in survivors versus non-survivors (p = 0.007 vs. p = 0.024, respectively). Higher plasma/serum creatinine levels, higher lactate levels, and lower arterial pH were all associated with patients receiving RRT (all p < 0.05). Overall mortality was 22% (20 out of 92 patients) and did not differ between the RRT and non-RRT groups.
CONCLUSION
Mortality is high in ICU patients with metformin-associated hyperlactatemia/LA. Unexpectedly, higher ingested metformin dose and plasma/serum creatinine were associated with a better outcome. Survival was similar in patients with or without need for RRT.
Topics: Humans; Hyperlactatemia; Acidosis, Lactic; Retrospective Studies; Creatinine; Metformin; Intensive Care Units; Lactates; Hypoglycemic Agents
PubMed: 36652938
DOI: 10.1159/000528252 -
European Review For Medical and... Feb 2013Metformin is known to be rarely associated with lactic acidosis, a serious condition with a poor prognosis. (Review)
Review
BACKGROUND
Metformin is known to be rarely associated with lactic acidosis, a serious condition with a poor prognosis.
AIM
To review the National Pharmacovigilance Network of the Italian Medicines Agency reporting cases of metformin-associated lactic acidosis.
MATERIALS AND METHODS
The National Pharmacovigilance Network of the Italian Medicines Agency, was searched for cases of lactic acidosis that occurred in a 10 years period (from November 2001 to October 2011). Data were analyzed, to identify associated clinical features. A systematic literature research was performed to identify other large case series on metformin associated lactic acidosis.
RESULTS
Metformin was the antidiabetic drug most frequently associated with lactic acidosis in the assessed period. Metformin-associated lactic acidosis was the most frequent serious adverse reaction related to metformin reported to the national authority (18.2% of all 650 adverse drug reactions reported). There were 59 cases of metformin-associated lactic acidosis (mortality rate of 25.4%). In most patients (89.8%) there was at least one risk factor for the occurrence of lactic acidosis. The predictors of death were low arterial blood pH and absence of acute renal failure. The systematic research of the literature identified only six case-series with more than 30 patients.
CONCLUSIONS
This is the second largest case series ever reported on metformin-associated lactic acidosis. We confirmed that this rare complication of metformin is frequently fatal. Death can be predicted when the patient arrive in the hospital with low pH and, not intuitively, if the patient has no acute kidney injury. Risk minimisation measures taken at national level to prevent this serious complication are described.
Topics: Acidosis, Lactic; Adverse Drug Reaction Reporting Systems; Aged; Female; Health Surveys; Hospitalization; Humans; Hypoglycemic Agents; Italy; Male; Metformin; Middle Aged; Prognosis; Risk Factors; Time Factors
PubMed: 23436666
DOI: No ID Found -
California Medicine Dec 1964
-
European Journal of Pediatrics Apr 2021Lactic acidosis is a common complication of status asthmaticus in adults. However, data is sparse in children. The aim of this study was to describe the prevalence and... (Observational Study)
Observational Study
Lactic acidosis is a common complication of status asthmaticus in adults. However, data is sparse in children. The aim of this study was to describe the prevalence and risk factors for lactic acidosis in children hospitalised for acute moderate or severe asthma. A total of 154 children 2-17 years of age were enrolled in a prospective observational study conducted in a tertiary hospital. All had capillary blood gas assessment 4 h after the first dose of salbutamol in hospital. The primary endpoint was the prevalence of lactic acidosis. Potential contributing factors such as age, sex, BMI, initial degree of asthma severity, type of salbutamol administration (nebuliser or inhaler), steroids, ipratropium bromide, and glucose-containing maintenance fluid represented secondary endpoints. All in all, 87% of patients had hyperlactatemia (lactate concentration > 2.2 mmol/l). Lactic acidosis (lactate concentration > 5 mmol/l and anion gap ≥ 16 mmol/l) was observed in 26%. In multivariate analysis, age more than 6 years (OR = 2.8, 95% CI 1.2-6.6), glycemia above 11 mmol/l (OR = 3.2 95% CI 1.4-7.4), and salbutamol administered by nebuliser (OR = 10, 95% CI 2.7-47) were identified as risk factors for lactic acidosis in children with moderate or severe asthma.Conclusion: Lactic acidosis is a frequent and early complication of acute moderate or severe asthma in children. What is Known: • Lactic acidosis during acute asthma is associated with b2-mimetics administration. • Salbutamol-related lactic acidosis is self-limited but important to recognise, as compensatory hyperventilation of lactic acidosis can be mistaken for respiratory worsening and lead to inappropriate supplemental bronchodilator administration. What is New: • Lactic acidosis is a frequent complication of acute asthma in the paediatric population. • Age older than 6 years, hyperglycaemia, and nebulised salbutamol are risk factors for lactic acidosis during asthma.
Topics: Acidosis, Lactic; Adolescent; Albuterol; Asthma; Child; Child, Preschool; Humans; Prevalence; Risk Factors
PubMed: 33089387
DOI: 10.1007/s00431-020-03834-x -
The Cochrane Database of Systematic... Apr 2010Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2... (Review)
Review
BACKGROUND
Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age.
OBJECTIVES
To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies.
SEARCH STRATEGY
A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators.
SELECTION CRITERIA
Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy.
DATA COLLECTION AND ANALYSIS
The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data.
MAIN RESULTS
Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies.
AUTHORS' CONCLUSIONS
There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.
Topics: Acidosis, Lactic; Cohort Studies; Contraindications; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incidence; Lactic Acid; Metformin; Prospective Studies; Risk
PubMed: 20393934
DOI: 10.1002/14651858.CD002967.pub4 -
BMJ Case Reports Feb 2022A 17-year-old man was admitted to the paediatric intensive care unit 2 hours following an intentional ingestion of unknown substances. In the first 23 hours of...
A 17-year-old man was admitted to the paediatric intensive care unit 2 hours following an intentional ingestion of unknown substances. In the first 23 hours of hospitalisation, lactate levels remained elevated at 2-4 mmol/L, during the 24th hour, he developed lactic acidosis with lactate levels increasing from 4 to 16 mmol/L. His neurological status declined, requiring orotracheal intubation. Central and arterial access were obtained, and vasoactive infusions were initiated for haemodynamic support. Due to increasing lactate levels (maximum level >24 mmol/L) and haemodynamic instability, a dialysis line was inserted, and continuous renal replacement therapy (CRRT) was initiated. The lactic acidosis resolved over 10 hours. Serum ibuprofen level subsequently resulted at 841 µg/mL (reference range 10-50). Few reported cases discuss the sequela of large quantity ibuprofen ingestion leading to severe lactic acidosis and multiorgan system failure. Early intervention with CRRT may reverse acidosis, stabilise haemodynamics and halt secondary organ failure.
Topics: Acidosis, Lactic; Adolescent; Child; Continuous Renal Replacement Therapy; Drug Overdose; Humans; Ibuprofen; Male; Metformin; Renal Dialysis
PubMed: 35131772
DOI: 10.1136/bcr-2021-244281 -
Communications Biology Jul 2023Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the...
Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.
Topics: Humans; Fructose-1,6-Diphosphatase Deficiency; Fructose-Bisphosphatase; Fructose; Acidosis, Lactic; Phenotype; Genotype; Hypoglycemic Agents
PubMed: 37507476
DOI: 10.1038/s42003-023-05160-y -
Diabetes, Obesity & Metabolism Nov 2017
Topics: Acidosis, Lactic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin
PubMed: 28474371
DOI: 10.1111/dom.12994