Biguanides and lactic acidosis:unraveling the complex relationship

Biguanides,such as metformin,have long been established as frontline medications for the management of type 2 diabetes due to their glucose-lowering effects and favorable safety profiles.However,concerns regarding the risk of lactic acidosis associated with biguanide use have sparked considerable debate and scrutiny.This research article aims to provide a comprehensive analysis of the relationship between biguanides,particularly metformin,and lactic acidosis.We delve into the underlying mechanisms,epidemiological evidence,risk factors,clinical manifestations,diagnostic considerations,and management strategies related to biguanide-induced lactic acidosis.Additionally,we explore recent research developments,controversies,and future directions in this critical area of pharmacovigilance and clinical practice.

Diarrhea and Acute Renal Injury Culminating in Metformin-Induced Lactic Acidosis

Background: Metformin (M) is an effective first-line hypoglycemic agent in obese type 2 diabetes mellitus due to its low cost and safety profile. The Case: A 66-year-man presented with shock due to lactic acidosis induced by M-supersaturation subsequent to acute renal failure following infective diarrhea. The drug has been used, by this patient, for >10 years without complication. Physical examination, laboratory tests, radiological investigations and blood cultures did not show evidence of new cardiac, hepatic and septic insult. Despite discontinuation of M and 2-days of aggressive hydration, bicarbonate infusions and pressors;toxic levels of the drug persisted and shock-state culminated in severe and oliguric renal failure with serum urea and creatinine up to 50 mmol/L and 1270 umol/L, respectively. Hence, continuous venovenous hemodiafiltration (CVVHDF) was used, for 16-hours, to remove the drug, correct his acidosis and support his severe renal complications. Hours after the procedure;drug level, lactic acidosis and its associated shock improved followed by gradual renal recovery. The patient was discharged after 6 days and serum creatinine reached his base line (180 umol/L) 2 weeks later. The drug was not recommended for his future use. Conclusion: M-induced lactic acidosis, should be considered in assessment of shock in M-treated patients and management of unstable patients indicates early-use of CVVHDF.

糖尿病乳酸性酸中毒(Diaberic lactic acidosis DLA)的治疗

糖尿病患者可因体内乳酸累积而发生乳酸性酸中毒,如不及时诊断和治疗,可发生死亡。乳酸是葡萄糖的中间代谢产物。葡萄糖的分解代谢包括葡萄糖的有氧氧化和葡萄糖的无氧酵解。前者是葡萄糖在正常有氧条件下彻底氧化产生二氧化碳和水,它是体内糖分解产能的主要途径,大多数组织能获得足够的氧气以供有氧氧化之需而很少进行无氧糖酵解;而后者是葡萄糖在无氧条件下分解成为乳酸,它虽然已非主要代谢途径而且产能有限,但仍是重要的代谢方式并具有病理生理意义。

EVALUATION OF MITOCHONDRIAL ENCEPHALOMYOPATHY WITH LACTIC ACIDOSIS AND STROKE-LIKE EPISODES WITH MAGNETIC RESONANCE IMAGING AND PROTON MAGNETIC RESONANCE SPECTROSCOPY

Objective To study the characteristics of spectra on proton magnetic resonance spectroscopy （^1H-MRS） and its value in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes （MELAS）. Methods Seven clinically diagnosed patients with MELAS underwent magnetic resonance imaging （MRI） and ^1H-MRS examinations. The ^1H-MRS techniques, characteristics of the spectra, and its correlation with the laboratory tests were analyzed. Reaults Cerebral abnormalities were revealed in all 7 patients on conventional MR images, and most abnormal signals were observed in bilateral occipital, parietal, and temporal lobes. We found 4 cases with basal ganglia involvement, 2 cases with mild frontal lobe lesions, and 1 case with involvement of lateral cerebral peduncles and thalami. Additionally, 1 patient was involved with left insular lobe. Spectra from prominent lesions in brain parenchyma showed lactate doublet peak in 6 patients, 3 of whom were also noted lactate peak in ventricular cerehrospinal fluid （CSF）. Conclusion ^1H-MRS may provide more direct information about the metabolism changes, which aids to affirm the diagnosis, and may replace the conventional invasive method of quantifying lactate in CSF.

Mucosal necrosis of the small intestine in myopathy,encephalopathy,lactic acidosis,and stroke-like episodes syndrome

This report presents a case of massive mucosal necrosis of the small intestine in a patient with mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes(MELAS),which particularly affects the brain,nervous system and muscles.A 45-year-old Japanese female,with an established diagnosis of MELAS,presented with vomiting.Computed tomography showed portomesenteric venous gas and pneumatosis intestinalis.She underwent a resection of the small intestine.A microscopic study showed necrosis of the mucosa and vacuolar degeneration of smooth muscle cells in the arterial wall.Immunohistochemistry showed anti-mitochondrial antibody to be highly expressed in the crypts adjacent the necrotic mucosa.The microscopic and immunohistochemical findings suggested the presence of a large number of abnormal mitochondria in MELAS to be closely linked to mucosal necrosis of the small intestine.

Metformin associated lactic acidosis in Auckland City Hospital 2005 to 2009

AIM： To determine the incidence, clinical characteristics and outcomes of patients with metformin associated lactic acidosis （MALA）.METHODS： Auckland City Hospital drains a population of just over 400000 people. All cases presenting with metabolic acidosis between July 2005 and July 2009 were identifed using clinical coding. A retrospective case notes review identifed patients with MALA. Prescribing data for metformin was obtained from the national pharmaceutical prescribing scheme.RESULTS： There were 42 cases of metabolic lactic acidosis over 1718000 patient years. There were 51000 patient years of metformin prescribed to patients over the study period. There were thirty two cases of lactic acidosis due to sepsis, seven in patients treated with metformin. Ten cases of MALA were identified. The incidence of MALA was estimated at 19.46 per 100000 patient year exposure to metformin. The relative risk of lactic acidosis in patients on metformin was 13.53 （95%CI： 7.88-21.66） compared to the general population. The mean age of patients with MALA was 63 years, range 40-83 years. A baseline estimated glomerular fltration rate was obtained in all patients and ranged from 23-130 mL/min per 1.73 m^2. Only two patients had chronic kidney disease G4.Three patients required treatment with haemodialysis. Two patients died.

Clinical,pathological and genetic study of a kindred of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes

The first description of a syndrome including stroke-like episodes, lactic acidaemia, and ragged red fibres, was reported by Shapira et al in 1975. 1 Pavlakis et al 2 described further cases, introduced the acronym MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), and suggested that this represented a distinct mitochondrial disease phenotype. In 1990, Goto et al 3 identified A3243G mutation in the transfer RNA (tRNA) leucine (UUR) gene in some patients with MELAS. Although this mutation has now been established to be the commonest mtDNA defect it is often misdiagnosed. Here we report a kindred of MELAS including a mother and a son. Clinical, pathological and genetic studies are proceeding.

Warburg effect mimicking inborn errors of metabolism in childhood hematologic malignancies:A case-based systematic review

BACKGROUND Type B lactic acidosis and hypoglycemia can occur in various pediatric conditions.In young children with a history of fasting preceding these metabolic derangements,inborn errors of metabolism should be primarily considered.However,the Warburg effect,a rare metabolic complication,can also manifest in children with hematologic malignancies.Only a few reports of this condition in children have been published in the literature.AIM To identify the clinical course,treatment strategies,and outcomes of childhood hematologic malignancies with type B lactic acidosis.METHODS We performed a comprehensive search of the PubMed,Scopus,and Cochrane databases without any time restriction but limited to English language articles.The databases were last accessed on July 1st,2023.RESULTS A total of 20 publications were included in the analysis,all of which were case reports or case series.No higher quality evidence was available.Among children with hematologic malignancies and Warburg effect,there were 14 cases of acute lymphoblastic leukemia and 6 cases of non-Hodgkin’s lymphoma including our illustrative case.Lactic acidosis occurred in 55%of newly diagnosed cases and 45%of relapsed cases.The mean age was 10.3±4.5 years,and 80%of cases were male.The mean serum lactate was 16.9±12.6 mmol/L,and 43.8%of the cases had concomitant hypoglycemia.Lactic acidosis initially subsided in 80%of patients receiving chemotherapy compared to 60%in the contrast group.The mortality rate of newly diagnosed cases was 45.5%,while the relapsed cases represented a 100%mortality rate.All 8 patients reported before 2001 died from disease-related complications.However,patients described in reports published between 2003 and 2023 had a 54.5%rate of complete remission.CONCLUSION This complication has historically led to fatal outcome;however,patients who received chemotherapy showed a more favorable response.Therefore,it is crucial to promptly initiate specific treatment in this context.

Metformin does not improve survival in patients with hepatocellular carcinoma

AIM: To assess whether metformin, which has a chemopreventive effect in chronic liver disease, has any chemotherapeutic effect in hepatocellular carcinoma.

Acute esophageal necrosis caused by alcohol abuse

Acute esophageal necrosis (AEN) is extremely rare and the pathogenesis of this is still unknown. We report a case of AEN caused by alcohol abuse. In our case, the main pathogenesis could be accounted for low systemic perfusion caused by severe alcoholic lactic acidosis. After the healing of AEN, balloon dilatation was effective to manage the stricture.

characteristics of intestinal pseudo-obstruction in patients with mitochondrial diseases

AIM: To reveal the frequency, characteristics and prognosis of chronic intestinal pseudo-obstruction (CIP) in mitochondrial disease patients. METHODS: Between January 2000 and December 2010, 31 patients (13 males and 18 females) were di-agnosed with mitochondrial diseases at our hospital. We conducted a retrospective review of the patients' sex, subclass of mitochondrial disease, age at onset of mitochondrial disease, frequency of CIP and the age at its onset, and the duration of survival. The age at onset or at the first diagnosis of the disorder that led to the clinical suspicion of mitochondrial disease was also examined. RESULTS: Twenty patients were sub-classified with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), 8 with chronic progressive external ophthalmoplegia (CPEO), and 3 with myoclonus epilepsy associated with ragged-red fibers (MERRF). Nine patients were diagnosed with CIP, 8 of the 20 (40.0%) patients with MELAS, 0 of the 8 (0.0%) patients with CPEO, and 1 of the 3 (33.3%) patients with MERRF. The median age (range) at the diagnosis and the median age at onset of mitochondrial disease were 40 (17-69) and 25 (12-63) years in patients with CIP, and 49 (17-81) and 40 (11-71) years in patients without CIP. During the survey period, 5 patients (4 patients with MELAS and 1 with CPEO) died. The cause of death was cardiomyopathy in 2 patients with MELAS, cerebral infarction in 1 patient with MELAS, epilepsy and aspiration pneumonia in 1 patient with MELAS, and multiple metastases from gastric cancer and aspiration pneumonia in 1 patient with CPEO. CONCLUSION: Patients with CIP tend to have disorders that are suspected to be related to mitochondrial diseases at younger ages than are patients without CIP.

Myopathological features in MELAS syndrome without significant changes in muscle biopsy pathology

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes （MELAS） are common types of mitochondrial encephalomyopathy. The involved muscular pathology is characterized by typical changes of mitochondrial abnormalities. Gene screening has been the gold diagnostic standard for MELAS diagnosis. This study presents three primary MELAS patients, with an age of onset from 13 to 18 years, including one patient with seizure, and two with headache and vomiting. All patients had a family history of disease, with maternal inheritance. Cerebral magnetic resonance imaging revealed abnormally high signals in T2-weighted images： temporal lobe in three cases, occipital lobe in two cases, and parietal lobe in one case. Migrating stroke-like lesions were confirmed in one patient. Muscle biopsy revealed several strongly succinate dehydrogenase-reactive vessels scattered in muscle sections of three patients, but ragged-red fibers and cytochrome c oxidase-negative/dense （COX-/＋） fibers were not observed. Mitochondrial DNA A3243G mutation was identified in all three cases. MELAS syndrome has obvious clinical heterogeneity, and muscle weakness was not prominent in some of the cases. Muscle pathological changes did not accompany ragged-red fibers or COX-/＋ fibers, but succinate dehydrogenase- reactive vessels are important for MELAS diagnosis.

Metformin toxicity: A meta-summary of case reports

BACKGROUND Metformin is arguably the most commonly prescribed oral hypoglycemic agent for the management of diabetes.Due to the lack of randomized control trials,most of the data pertaining to the clinical course,therapeutic interventions and outcomes of patients with metformin induced toxicity has come from case reports or series.AIM To analyse the symptomology,clinical interventions and outcomes of patients presenting with severe metformin toxicity by reviewing the published case reports and series.METHODS We performed a systematic search from PubMed,Science Direct,Reference Citation Analysis(https://www.referencecitationanalysis.com/)and Google Scholar databases using the terms“metformin”AND“toxicity”OR“overdose”OR“lactic acidosis”OR“hyperlactatemia”.The inclusion criteria were:(1)Case reports or case series with individual patient details;and(2)Reported toxicity or overdose of metformin in adults,published in the English language.Data regarding baseline demographics,clinical presentation,therapeutic interventions,intensive care unit course and overall outcome were collected.RESULTS Two hundred forty-two individual cases were analysed,from 158 case reports and 26 case series,with a cumulative mortality of 19.8%.214(88.4%)patients were diabetics on metformin.57(23.6%)had acute ingestion,but a great majority(76.4%)were on metformin in therapeutic doses when they developed toxicity.Metformin associated lactic acidosis(MALA)was the most commonly reported adverse effect present in 224(92.6%)patients.Most of the patients presented with gastrointestinal and neurological symptoms and a significant number of patients had severe metabolic acidosis and hyperlactatemia.The organ support used was renal replacement therapy(RRT)(68.6%),vasopressors(58.7%)and invasive mechanical ventilation(52.9%).A majority of patients(68.6%)received RRT for toxin removal,renal dysfunction and correction of MALA.Patients with lowest pH and highest serum lactate and metformin levels also had favourable outcomes with use of RRT.CONCLUSION Most of the reported cases were on therapeutic doses of metformin but developed toxicity after an acute deterioration in renal functions.These patients may develop severe lactic acidosis,leading to significant morbidity and need for organ support.Despite severe MALA and the need for multiple organ support,they may have good outcomes,especially when RRT is used.The dose of metformin,serum pH,lactate and metformin levels may indicate the severity of toxicity and the need for aggressive therapeutic measures but may not necessarily indicate poor outcomes.

Effect of Metformin on Lactate Metabolism in Normal Hepatocytes under High Glucose Stress in Vitro

Objective To study the effect of metformin on lactate metabolism in hepatocytes in vitro under high glucose stress.In vitro LO2 cells,liver cells were randomly divided into blank control group,25 tendency/L glucose solution,27 tendency/L glucose solution,29 tendency/L glucose solution,31 tendency/L glucose solution,33 tendency/L glucose solution,35 tendency/L glucose solution treatment group,the optimal concentation of 31 tendency after L,use 30 tendency for L metformin solution,and then divided into blank control group,the optimal concentration of glucose solution,normal liver cells+metformin solution normal liver cells.The optimal concentration of glucose solution normal liver cells+metformin solution respectively in the 12h,24 h,48 h on cell count plate to calculate the mumber of liver cells,and using lactic acid determination kit the optimal concentration of glucose solution+normal liver cells and normal liver cells+the optimal concentration of glucose solution+metformin solution respectively in the 12 h,24 h,48 h of cell cultures of lactic acid value.There was no significant change in the lactic acid concentration but significant increase in the number of suviving hepatocytes in the high-glycemic control group compared with that in the high-glycemic control group without metformin.Metformin has no significant effect on lactic acid metabolism of hepatocytes under high glucose stess in vito,and has a protective effect on hepatocytes under high glucose stress.Based on this,it is preliminanily believed that metformin is not the direct factor leading to diabetic lactic acidosis.

Detection of A3243G point mutation in mitochondrial DNA from 10 cases of MELAS

Objective To search for A3243G point mutations in mitochondrial DNA (mtDNA) from 10 cases of mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS) Methods Using PCR restriction analysis, we investigated A3243G point mutations in mtDNA of muscle and/or blood cells from 10 patients and their 8 maternal relatives We also quantitated the A3243G mtDNA in samples harboring the mutation Results A3243G point mutations were identified in all muscle and/or blood samples from 10 MELAS patients The proportion of mutant mtDNA was 10 8%-47 8% in blood (7 cases), and 39 4%-67 7% in muscle (5 cases) This ratio was invariably higher in muscle than in blood from two patients whose blood and muscle samples were both available Younger patients usually carried higher proportions of A3243G mutant mtDNA in blood Eight maternal relatives from 6 families were also examined Maternal transmission of the disease could be identified in one family No A3243G point mutations were found in mothers' blood from 3 families and siblings' blood from 2 families Conclusions All 10 MELAS patients were found to have the mtDNA A3243G mutation in their muscle and/or blood The A3243G mutation seems to be sporadic in 5 of the families examined, suggesting the mechanism of de novo mutation for the pathogenesis of their MELAS syndrome

Severe and lethal adverse reactions of linezolid--a summary analysis of case reports

A systematic summary was used to evaluate case reports of adverse drug reactions(ADRs)caused by linezolid,and to explore the effects and severity on human organs or systems in the real world.The databases,such as PubMed,Embase,Cochrane Library,and CINAHL,were searched using“linezolid”+“case reports”as search terms from the establishment of each database to 31 st December 2019,and the case reports on ADRs related to linezolid were collected.A total of 159 case reports were finally included in the analysis,including 189 patients.The ratio of male to female was 0.89:1,and the average age was(52.42±23.43)years old.The results showed that linezolid-related severe ADRs mainly occurred in the nervous system(n=86)and blood system(n=44),followed by the metabolic system(n=31)and gastrointestinal system(n=18).Other systems reported less frequently were the skin tissue(n=6),renal and urinary system(n=3),cardiovascular systems(n=2),and hepatobiliary system(n=2).The most common linezolid-related ADRs were serotonin syndrome(n=40),followed by optic neuropathy(n=25)and thrombocytopenia(n=22).The most severe ADR was lactic acidosis(n=29),and its death rate was as high as 31.0%.In the blood system ADRs,11 cases had underlying diseases of renal impairment,and four of them died.Moreover,22 cases with thrombocytopenia were mainly elderly over 65 years old(n=17),and there were also one infant and one child with thrombocytopenia.We first reported that lactic acidosis and blood system ADRs mostly occurred within 28 d,and the nervous system ADRs mostly occurred after 28 d.Besides,irreversible auditory neuropathy(n=1),hypophosphatemia(n=1),bradycardia(n=1),and tooth discoloration mostly occurring in minors(n=5)were the linezolid-related ADRs,which were not described in the instructions,related guidelines,and clinical trials of linezolid.The most severe linezolid-related ADRs was lactic acidosis that occurred within 28 d.Renal damage and special populations might be the main risk factors in the blood system ADRs.Minor linezolid-related ADRs were rare,while there were still some cases of auditory neuropathy,hypophosphatemia,bradycardia,and tooth discoloration.