Alcoholic Ketosis

We prospectively studied 23 episodes of suspected alcoholic ketosis in order to learn whether there was objective evidence of the patients having stopped drinking ethanol a few days before admission, and of being starved. Eight patients had moderate ketosis (plasma 3-hydroxybutyrate 4.1-7.8 mmol/liter); seven patients had mild ketosis (2-4 mmol/liter); and eight had little or no ketosis (less than 2 mmol/liter). The latter eight patients had mainly lactic acidosis (plasma lactate 2.0-13.3 mmol/liter). Most of the ketotic patients did not have ethanol detected in their blood. The presence of starvation was supported by the finding of subnormal plasma triiodothyronine levels (less than 90 micrograms/dl) in six of seven ketotic patients (average 60 micrograms/dl for all seven). The ketotic patients usually had low-normal plasma insulin levels (3- 16 microU/ml), as is common in starvation. Our findings support the previously undocumented belief that most patients with alcoholic ketosis did stop drinking ethanol some time before admission, and that starvation is a major pathogenetic factor in the disorder.     

Lactic acidosis in diabetic patients.

Plasma lactate and beta-hydroxybutyrate concentrations were measured during episodes of ketoacidosis and lactic acidosis in diabetics. In 39 patients with ketoacidosis, with a mean plasma beta-hydroxybutyrate concentration of 12.4 millimols/liter, the plasma lactate concentration was less than 3.6 millimols/liter in 28 and moderately elevated in 11. In seven of the latter, coexisting lactic acidosis had been suspected clinically. In these 39 patients, there was no correlation between plasma lactate and beta-hydroxybutyrate concentrations. In six of ten episodes of presumed and later proved lactic acidosis, despite negative or weakly positive serum reactions with sodium nitroprusside, the plasma beta-hydroxybutyrate concentration was elevated. Although positive, the serum reaction with nitroprusside was also misleadingly weak in five of 39 patients with ketoacidosis, including three with plasma lactate concentrations less than 3 millimols/liter.     

Cholesterol-lowering effects of a 10 mg daily dose of lovastatin in patients with initial total cholesterol levels 200 to 240 mg/dl (5.18 to 6.21 mmol/liter)

Subjects with plasma cholesterol levels greater than 240 mg/dl (6.21 mmol/liter) and those with greater than 200 mg/dl (5.18 mmol/liter) who have coronary artery disease, or those with 2 risk factors for ischemic heart disease who do not respond to a hypocholesterolemic diet should all be treated. Lovastatin, which is an inhibitor of hydroxymethygluteryl coenzyme A reductase, is a new agent for treating hypercholesterolemia and is administered in a dose of 20 to 80 mg/day. A study was conducted in which only 10 mg of lovastatin was given to 28 subjects with plasma cholesterol of 200 to 240 mg/dl (5.18 to 6.21 mmol/liter). Cholesterol plasma levels decreased in 19% and low-density lipoprotein cholesterol decreased by 24% from baseline levels after 20 weeks of treatment. All 28 patients decreased their cholesterol values to less than 200 mg% (5.18 mmol/liter), and only 1 had a low-density lipoprotein level greater than 130 mg% (3.36 mmol/liter) at termination of the study. Achievement of desirable values of cholesterol with 10 mg of lovastatin was accompanied by less adverse effects and with significant financial saving. The calculated saving for lovastatin consumers in the USA could be an amount of $60,000,000. Thus, it is recommended that this drug be manufactured in 10 mg tablets.     

D-lactate encephalopathy

Although D-lactate is not a product of human intermediary metabolism, absorption of D-lactate produced by abnormal intestinal bacteria can cause systemic acidosis in patients who have undergone gastrointestinal surgery, particularly jejunoileal bypass. In order to learn more about the prevalence of D-lactate encephalopathy, its occurrence in other disorders, and how well D-lactate concentration correlates with clinical symptoms, serum D-lactate levels were determined in several specific populations. D-lactate was undetectable (less than 0.5 mmol/liter) in 72 healthy volunteers and 57 obese persons. In 33 patients who had jejunoileal bypass, 16 reported symptoms consistent with D-lactate encephalopathy since surgery. Nine of these 16 had D-lactate levels greater than 0.5 mmol/liter (range 0.7 to 11.5 mmol/liter). Levels of D-lactate fluctuated over time, and in two patients, markedly elevated levels correlated with an encephalopathy accompanied by hyperchloremic metabolic acidosis and elevated anion gap. In 470 randomly chosen hospitalized patients, D-lactate level greater than 0.5 mmol/liter was found in 13 (2.8 percent), and 60 percent of these had a history of gastrointestinal surgery or disease. It is concluded that elevated serum D-lactate levels are relatively common in patients with jejunoileal bypass, and although more rare, occur in other gastrointestinal disorders as well. The symptoms of D-lactate encephalopathy are quite sensitive, but not necessarily specific for this disorder.     

Lactic acidosis associated with standard dose linezolid in a kidney recipient with impaired renal function

Severe lactic acidosis, a mitochondrial toxicity caused by the recommended standard dosage of linezolid (LZD), may occur in patients with impaired renal function. We describe an adult male who underwent kidney transplantation with stably impaired renal function, severe dyspnea, and abdominal discomfort. He received a standard oral dose of LZD (600 mg twice daily) and azithromycin for three weeks with a reduced immunosuppressant dose due to pulmonary non-tuberculosis mycobacterial infection. He was alert and afebrile, with a blood pressure of 140/60 mmHg. Pertinent laboratory data showed: pH 7.12, PaCO2 13.6 mmHg; HCO3- 4.3 mmol/L and serum lactate 18.4 mmol/L. His trough serum LZD concentration reached toxic levels (21.4 μg/mL). With hemodialysis, his clinical symptoms improved, with a decline in serum LZD (9.8μg/mL) and lactate (3.2 mmol/L). Chronic standard dose LZD in patients with impaired renal function can lead to life-threatening lactic acidosis, especially in coexisting conditions that reduce LZD metabolism.     

Increased osmolal gap in alcoholic ketoacidosis and lactic acidosis

OBJECTIVE: To determine whether an elevated osmolal gap is specific for toxic alcohol ingestion. DESIGN: Cross-sectional. SETTING: Emergency room and medical and surgical inpatient wards at a university-affiliated hospital. PATIENTS: Twenty-three patients with lactic acidosis, 19 with alcoholic ketoacidosis, and 10 randomly selected controls. MEASUREMENTS AND MAIN RESULTS: Calculated and measured serum osmolality was determined in all study participants. The osmolal gap was increased in patients with lactic acidosis (17.4 +/- 5.4 mmol/kg) and alcoholic ketoacidosis (26.9 +/- 7.6 mmol/kg) when compared with controls (-1.7 +/- 1.7 mmol/kg, P less than 0.05 for both comparisons). When ethanol was included in the calculation, the osmolal gap remained elevated in the lactic acidosis (10.3 +/- 2.0 mmol/kg) and alcoholic ketoacidosis (11.1 +/- 3.2 mmol/kg) groups (P less than 0.05 for both comparisons). CONCLUSIONS: The osmolal gap is often used as a screen for toxic alcohol ingestion. When calculating the osmolal gap, the contribution of ethanol should be considered. An elevated osmolal gap is not specific for toxic alcohol ingestion, as the osmolal gap was elevated in patients with lactic acidosis and alcoholic ketoacidosis. These two conditions should be considered when using the osmolal gap to design therapy (for example, hemodialysis) in the setting of anion gap metabolic acidosis and suspected toxic alcohol ingestion.     

Usefulness of parental serum total cholesterol levels in identifying children with hypercholesterolemia.

It was hypothesized that healthy children with high cholesterol levels may have parents who exceed acceptable cholesterol levels established by the National Cholesterol Education Program. One hundred sixty families (320 parents, 263 children aged 3 to 10 years) were evaluated for total cholesterol and other risk factors. Before the study, almost half of the parents had not had serum total cholesterol measured. The odds ratio for a child having a total cholesterol greater than or equal to 5.17 mmol/liter (200 mg/dl) was 13.6:1 (confidence interval 5.7 to 32.5) for a child with at least 1 parent having cholesterol greater than or equal to 6.20 mmol/liter (240 mg/dl) versus a child whose parents had low total cholesterol. Testing only children who had at least 1 parent with a total cholesterol greater than or equal to 5.17 mmol/liter (200 mg/dl) had a sensitivity of 98% for detecting children's total cholesterol greater than or equal to 5.17 mmol/liter. It is concluded that parental total cholesterol is useful in identifying children with high total cholesterol levels. Pediatricians may identify a large number of parents with hypercholesterolemia not previously recognized.     

Lactic acidosis in severe asthma

Twelve patients with severe asthma in whom lactic acidosis developed are presented. All had an arterial blood pH level lower than that expected for the measured partial pressure of arterial carbon dioxide, all had an abnormally large anion gap, and the blood lactate level exceeded 2.8 mmol/liter. Respiratory acidosis subsequently developed in eight patients, and six required intubation. Lactic acidosis can develop in patients with severe asthma. Such patients are in danger of the development of respiratory failure and must be treated vigorously and observed closely.     

Reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment

BACKGROUND: Lactic acidosis in metformin use is a widely recognised but rare side effect. Case reports usually describe elderly patients with conditions which in themselves can cause lactic acidosis or with known contraindications to metformin. We present cases of an elderly woman, a younger woman and a man who developed serious metformin-induced lactic acidosis in the absence of chronic renal impairment. RESULTS: Laboratory results showed acute renal failure in all patients. The pH was 6.77, 6.98 and 6.7, respectively, and lactate levels were 18.2, 18.4 and 11.7 mmol/l, respectively. Metformin plasma levels were 58, 57 and 39 mg/l. All patients received continuous veno-venous haemofiltration (CVVH), using bicarbonate as a buffer solution shortly after arrival on our ICU. In the subsequent hours, a steep decline in the plasma levels was observed, with a concomitant increase in pH. No other diagnoses were made, so we concluded that all patients were suffering from metformin-induced lactic acidosis. Despite the severity of the metabolic acidosis, both female patients survived. Our male patient died after a prolonged stay in the ICU, but this was not related to metformin. CONCLUSION: Metformin-induced lactic acidosis does exist. Metformin-induced lactic acidosis may occur in patients with previously normal renal function, even in young patients. Patients with extreme (lactic) metabolic acidosis caused by metformin can survive when CVVH treatment is initiated rapidly. Intercurrent symptoms or diseases that affect renal perfusion can precipitate lactic acidosis.     

Relation of the level of high-density lipoprotein subfractions to the presence and extent of coronary artery disease.

Plasma lipid profiles, including high-density lipoprotein (HDL) subfractions HDL2 and HDL3, were obtained in 115 men undergoing coronary angiography to assess the relation of lipid levels to coronary artery disease (CAD). CAD was present in 87 patients (76%) and absent in 28 (24%). The largest difference between the 2 groups were observed for HDL2 cholesterol, with a mean of 0.13 mmol/liter (5 mg/dl) in patients with CAD compared with 0.25 mmol/liter (10 mg/dl) in those without CAD (p less than 0.005). Smaller differences were found for HDL3 (1.02 mmol/liter [39 mg/dl] vs 1.19 mmol/liter [46 mg/dl]; p less than 0.005) and HDL (1.15 vs 1.42 mmol/liter [45 vs 55 mg/dl]; p less than 0.001) cholesterol, and apolipoprotein A-1 (1.37 vs 1.50 g/liter; p less than 0.01) and plasma triglycerides (1.79 vs 1.38 mmol/liter [159 vs 122 mg/dl]; p less than 0.05). No significant difference was found for plasma and low-density lipoprotein cholesterol, and apolipoprotein B levels. Simple regression analysis revealed that the most powerful independent variable associated with the extent of CAD was HDL2 cholesterol (Spearman rho = 0.311; p less than 0.001). Stepwise multiple regression analysis proved HDL2 cholesterol and age to be the strongest predictors of extent of CAD. The level of HDL2 cholesterol was reasonably well correlated with HDL cholesterol (r2 = 0.6; p less than 0.0001), but less so with plasma apolipoprotein A-1 (r2 = 0.4; p less than 0.0001). The data add to the growing body of information demonstrating an important association of HDL (and more specifically HDL2) with CAD in men.     

Ethylene glycol intoxication: evaluation of kinetics and crystalluria

Ethylene glycol and glycolate kinetics were studied in two cases of ethylene glycol intoxication with maximal ethylene glycol/glycolate concentrations of 40.9/26.8 and 56.4/22.4 mmol/liter, respectively. Both patients survived, but with prolonged renal failure, upon treatment with bicarbonate, ethanol, and hemodialysis. Glycolic acid was the major cause of the metabolic acidosis in both cases; lactate levels were only slightly elevated. Kinetic calculations showed that both ethylene glycol and glycolate were distributed in total body water with plasma half-lives of 8.4 and 7.0 hours, respectively. The half-life of ethylene glycol was increased more than 10-fold by ethanol treatment alone. Calcium oxalate monohydrate crystalluria was dominant in both cases, but in one was preceded by a short period with mainly dihydrate excretion; crystalluria was not present upon admission. Repetitive urine microscopy in search of needle- or envelope-shaped crystals should be performed when ethylene glycol intoxication is suspected.     

Glycolate Causes the Acidosis in Ethylene Glycol Poisoning and is Effectively Removed by Hemodialysis

ABSTRACT Six male patients with severe ethylene glycol poisoning were studied with respect to the origin of the metabolic acidosis. The plasma concentrations of ethylene glycol were 4–41 mmol/l and treatment included alkali, ethanol and hemodialysis. Plasma analysis by isotachophoresis and whole blood lactate determinations showed that glycolate (17.0–29.3 mmol/l), lactate (1.4–6.2 mmol/l) and β-hydroxybutyrate (≤1.8 mmol/l) were present in elevated concentrations contributing to the acidosis. Oxalate (≤0.33 mmol/l), glyoxylate (<0.2 mmol/l) and formate (<0.4 mmol/l) concentrations were negligible and did not contribute to any significant degree to the acidosis. The elevated plasma glycolate concentration was highly correlated to the anion gap (r=0.923) and the glycolate made up for 96.1% (n=6, range 84.7–108.8) of the increased anion gap. We conclude that glycolate accumulation is the main reason for the metabolic acidosis in ethylene glycol poisoning. The mean dialysator (1.6 m²) clearances of glycolate at a blood flow of 200 ml/min in two patients were 137 ml/min (n=9, SD±8, range 125–149) and 144 ml/min (n=11, SD±8, range 133–158). By applying first order kinetics during hemodialysis a volume of distribution of glycolate of 0.55 l/kg was found, assuming that the dialysator clearance equals the total body clearance of glycolate. Thus glycolate, the probable main metabolite of ethylene glycol, is efficiently removed by hemodialysis.     

Colonic lactate metabolism andd-lactic acidosis

d-Lactic acidosis is seen in patients with intestinal bypass or short bowels in whom colonic producedd-lactate accumulates. An intestinal bypassed patient withd-lactic acidosis had higher fecald-lactate (122.4 mmol/liter) andl-lactate (90.1 mmol/liter) than described before in humans.d-Lactate fluctuated between 0.5 and 3.1 mmol/liter in plasma (normal<0.1 mmol/liter) and between 1.1 and 52.8 mmol/liter in urine (normal<0.7 mmol/liter) within a few hours, indicating that the human organism do metabolize and excreted-lactate. The patient withd-lactic acidosis had a 10-fold increasedDl-lactate production from glucose in fecal homogenates compared to 14 healthy controls and a patient with intestinal bypass, who did not haved-lactic acidosis. A 67% carbohydrate (starch)-enriched diet resulted in a minor elevation of fecal and plasma lactate, whereas 50 + 100+150 g of ingested lactose increasedd-lactate in feces (84.0 mmol/liter) and plasma (2.3 mmol/liter) considerably in the patient withd-lactic acidosis. Intestinal prolongation (22 cm ileum) had a temporary effect on fecal and plasmad-lactate, but intestinal continuity was reestablished 26 months later becaused-lactic acidosis recurred (plasma 8.6 mmol/liter, urine 101.3 mmol/liter). Large amounts of lactulose (160 g/day) to 12 normal individuals increasedd-lactate to 13.6±3.5 mmol/liter in feces, but never increasedd-lactate in plasma or urine. Thein vitro fermentation of glucose in fecal homogenates increasedDl-lactate, which disappeared after complete metabolization of the glucose.l-Lactate was converted tod-lactate andvice versa, and both were degraded to the short-chain fatty acids acetate, propionate, and butyrate. An infrequent, but elevated ability of the colonic flora to produce lactate may be a prerequisite ford-lactic acidosis to occur and may explain why the syndrome is so seldom seen even in patients with intestinal bypass or short bowels. The suggestion thatd-lactate is not metabolized and hence accumulates is probably not valid.     

Glycolate Causes the Acidosis in Ethylene Glycol Poisoning and is Effectively Removed by Hemodialysis

Abstract Six male patients with severe ethylene glycol poisoning were studied with respect to the origin of the metabolic acidosis. The plasma concentrations of ethylene glycol were 4–41 mmol/l and treatment included alkali, ethanol and hemodialysis. Plasma analysis by isotachophoresis and whole blood lactate determinations showed that glycolate (17.0–29.3 mmol/l), lactate (1.4–6.2 mmol/l) and β-hydroxybutyrate (≤1.8 mmol/l) were present in elevated concentrations contributing to the acidosis. Oxalate (≤0.33 mmol/l), glyoxylate (<0.2 mmol/l) and formate (<0.4 mmol/l) concentrations were negligible and did not contribute to any significant degree to the acidosis. The elevated plasma glycolate concentration was highly correlated to the anion gap (r=0.923) and the glycolate made up for 96.1% (n=6, range 84.7–108.8) of the increased anion gap. We conclude that glycolate accumulation is the main reason for the metabolic acidosis in ethylene glycol poisoning. The mean dialysator (1.6 m²) clearances of glycolate at a blood flow of 200 ml/min in two patients were 137 ml/min (n=9, SD±8, range 125–149) and 144 ml/min (n=11, SD±8, range 133–158). By applying first order kinetics during hemodialysis a volume of distribution of glycolate of 0.55 l/kg was found, assuming that the dialysator clearance equals the total body clearance of glycolate. Thus glycolate, the probable main metabolite of ethylene glycol, is efficiently removed by hemodialysis.     

An Experimental model of phenformin-induced lactic acidosis in rats

Summary An experimental model of phenformininduced lactic acidosis was established in rats. Following a subtotal nephrectomy, renal failure developed (serum creatinine 4.5±0.1mg/100ml and 2.8±0.1 mg/100 ml on the 1st and 8th postoperative days respectively). Immediately after nephrectomy intra-peritoneal phenformin treatment, 16 mg/day, was commenced. Lactic acidosis developed progressively within 8 days, or earlier in the rats with the most severe renal insufficiency. The metabolic pattern was very similar to that observed in diabetic patients with a biguanide-induced lactic acidosis: on the 8th day, 2 h after the last phenformin injection, blood lactate was 10.8±1.0 mmol/1 (controls: 1.50±0.03); pyruvate was 0.56±0.06 mmol/1 (controls: 0.10±0.01) and blood pH: 7.00 ± 0.02 (vs 7.34±0.02); 3-hydroxybutyrate was 1.41±0.37 mmol/1 (vs 0.32 ±0.03); acetoacetate: 0.51±0.15 mmol/1 (vs 0.17 ±0.01), and free glycerol: 0.63 ±0.07 mmol/1 (vs 0.14 ±0.02). Increased concentrations of alanine (1.66±0.26 mmol/1, vs 0.48 ± 0.04 in controls) and low blood glucose levels (23± 8 mg/ 100 ml vs 70 ± 2, after a 12 hours fast) accompanied the lactic acidosis in spite of high glucagon levels (2030±170 pg/ml vs 108±10 in controls) and low insulin/glucagon molar ratio (0.19 vs 6.9 in controls). Normal rats, treated with phenformin at same doses, and nephrectomized rats injected with saline served as controls and remained free of lactic acidosis. Hydroxyphenformin (16 mg/day) injected in nephrectomized rats, was biologically inactive. Glucose production from¹⁴C-lactate was 425 ±85 mol/100 g body wt/h, vs 1050 ± 90 in control animals. Blood lactate specific activity declined more slowly in the lactic acidotic rats than in controls, suggesting that a decrease in lactate utilization contributed to hyperlactataemia more than an increased lactate production.     

Metformin therapy in patients with chronic kidney disease

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open‐label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15–40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250–2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3–5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.     

Vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency

Vitamin D insufficiency is common in patients with primary hyperparathyroidism (PHPT) and may be associated with more severe and progressive disease. Uncertainty exists, however, as to whether repletion of vitamin D should be undertaken in patients with PHPT. Here we report the effects of vitamin D repletion on biochemical outcomes over 1 yr in a group of 21 patients with mild PHPT [serum calcium <12 mg/dl (3 mmol/liter)] and coexistent vitamin D insufficiency [serum 25 hydroxyvitamin D [25(OH)D] <20 microg/liter (50 nmol/liter)]. In response to vitamin D repletion to a serum 25(OH)D level greater than 20 microg/liter (50 nmol/liter), mean levels of serum calcium and phosphate did not change, and serum calcium did not exceed 12 mg/dl (3 mmol/liter) in any patient. Levels of intact PTH fell by 24% at 6 months (P < 0.01) and 26% at 12 months (P < 0.01). There was an inverse relationship between the change in serum 25(OH)D and that in intact PTH (r = -0.43, P = 0.056). At 12 months, total serum alkaline phosphatase was significantly lower, and urine N-telopeptides tended to be lower than baseline values (P = 0.02 and 0.13, respectively). In two patients, 24-h urinary calcium excretion rose to exceed 400 mg/d, but the group mean 24-h urinary calcium excretion did not change. These preliminary data suggest that vitamin D repletion in patients with PHPT does not exacerbate hypercalcemia and may decrease levels of PTH and bone turnover. Some patients with PHPT may experience an increase in urinary calcium excretion after vitamin D repletion.     

Rationale and design of a secondary prevention trial of lowering normal plasma cholesterol levels after acute myocardial infarction: the Cholesterol and Recurrent Events trial (CARE)

Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol decreases the incidence of coronary heart disease in patients with elevated plasma cholesterol. However, it is not known whether patients with established coronary artery disease and normal plasma cholesterol can be benefited. Several previous prevention trials reviewed in this report found that patients who had plasma cholesterol levels at baseline in the upper portion of the eligibility range (e.g., greater than 240 mg/dl) received greater benefit from hypolipidemic diet or drug therapy than patients who had lower plasma cholesterol levels at baseline. The recent availability of drugs that are more potent and less prone to cause adverse reactions than previous regimens permits this important question to be addressed. The Cholesterol and Recurrent Events trial is testing whether pravastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, will decrease the sum of fatal coronary heart disease and nonfatal myocardial infarction (MI) in patients who have recovered from a MI and who have normal total cholesterol levels. Fatal cardiovascular disease and total mortality are important secondary end points. The trial is enrolling 4,000 men and women from 80 centers throughout North America, age 21 to 75 years, who have survived MI for 3 to 20 months, who have plasma total cholesterol less than 240 mg/dl (6.2 mmol/liter) and low-density cholesterol of 115 to 174 mg/dl (3.0 to 4.5 mmol/liter), and who are representative of the general population of patients with MI. Patients are randomized to either active or inactive drug therapy. Active therapy consists of pravastatin, 40 mg/day, designed to achieve an average decrease in low-density lipoprotein cholesterol of approximately 30%, and an increase in high-density lipoprotein of 5%. The average duration of follow-up will be greater than or equal to 5 years. To protect against a lower than expected rate of recurrent events, the trial will be continued until a predetermined fixed number of coronary heart disease events occurs in the entire cohort so that the original sensitivity of the trial will be maintained.