A rare etiology of hepatic steatosis associated with lactic acidosis: the toxicity of antiviral nucleoside analogues

We report three cases of hepatic steatosis associated with lactic acidosis occurring in HIV positive patients and due to a toxicity of antiviral nucleoside analogues. The clinico-pathological presentation was similar associating digestive signs (vomiting and abdominal pain), polypnea, lactic acidosis, a lethal clinical course, and an hepatomegaly with a diffuse macrovacuolar steatosis. The ultrastructural study performed in two cases showed mitochondrial alterations in hepatocytes. The toxicity of antiviral nucleoside analogues is due to a mitochondrial DNA polymerase inhibition. The incidence of this disease is actually low but probably underestimated. The diagnosis should be rapidly performed and the treatment immediatly interrupted.     

Fatal lactic acidosis possibly related to ganciclovir therapy in a renal transplant patient?

Ganciclovir is widely prescribed in renal transplant patients for the prevention or treatment of herpes and cytomegalovirus (CMV) infections. Side-effects are usually represented by hematological disorders, and particularly leucopenia. We report a case of severe and fatal lactic acidosis developing in a 76-year-old renal transplant woman, a few days after ganciclovir has been introduced to treat CMV pneumonia. Usual etiologies of lactic acidosis were ruled out. A high lactate/pyruvate molecular ratio was suggestive of a respiratory chain dysfunction. With the analogy to nucleoside analogues-related lactic acidosis, we suggest that ganciclovir may exceptionally be responsible for respiratory chain dysfunction and subsequent lactic acidosis, and we discuss potential risk factors in our patient.     

Fatal lactic acidosis in a patient infected by HIV and treated with stavudine and didanosine

We report a case of severe lactic acidosis in an human immunodeficiency virus (HIV)-infected patient treated with combination regimen of stavudine, didanosine and nevirapine. Antiretroviral nucleoside analogs are inhibitors of mitochondrial DNA polymerase gamma, resulting in the dysfunction of the mitochondrial respiratory chain. Despite symptomatic treatments and intravenous L-carnitine supplementation, lactic acidosis persisted, leading to multiorgan failure. The patient died 7 days after admission to the intensive care unit. Retrospective analysis of published cases showed neither specific nor predictive signs of outcome that is usually fatal, with no effective therapy to date. We therefore recommend determining blood lactate in patients with onset of unexplained general fatigue or digestive signs and to stop all antiretroviral treatments in the case of lactate increase.     

Fatal lactic acidosis and pancreatitis associated with ribavirin and didanosine therapy

Pancreatitis and lactic acidosis are severe and life-threatening adverse events associated with nucleoside analogue antiretroviral therapy used to treat HIV infection. The drug from this class most commonly associated with these adverse events is stavudine, although zidovudine and didanosine have also been implicated. Ribavirin is a nucleoside analogue used in combination with interferon alfa to treat hepatitis C. Because of similar mechanisms of action, the combination of these 2 drugs could potentially increase such toxicity. A case of fatal lactic acidosis and pancreatitis is described in an HIV-infected patient coinfected wtih hepatitis C on a didanosine-containing antiretroviral regimen after treatment of hepatitis C was initiated with ribavirin and pegylated interferon alfa-2b. Extreme caution should be exercised when didanosine and ribavirin are used concomitantly because of the increased risk of mitochondrial toxicity and the syndrome of severe metabolic acidosis with elevated lactic acid levels.     

Extracorporeal treatment with high-volume continuous venovenous hemodiafiltration and charcoal-based sorbent hemoperfusion for severe metformin-associated lactic acidosis

We present a case of a 49-year-old female with an alleged history of ingestion of approximately 100 tablets of metformin (850 mg each). Investigations revealed severe lactic acidosis with lactate levels of 13.5 mmol/L and pH of 7.17. This indicates severe toxicity and is associated with a high mortality. Charcoal-based sorbent hemoperfusion was done as a desperate effort, as patient continued to deteriorate despite supportive care and high-volume continuous venovenous hemodiafiltration. The patient survived despite metformin-associated lactic acidosis related to severe metformin toxicity.     

Absence of sustained hyperlactatemia in HIV-infected patients with risk factors for mitochondrial toxicity

BACKGROUND: The prevalence of asymptomatic hyperlactatemia among HIV-infected individuals has been reported to be 4% to 36%. This variability may reflect differences in the definition of and risk factors for hyperlactatemia and/or techniques for venous lactate collection. METHODS: We examined the prevalence of elevated venous lactate collected in accordance with Adult AIDS Clinical Trials Group (AACTG) guidelines among HIV-infected and nucleoside analogue-treated subjects with risk factors associated with hyperlactatemia. Sustained hyperlactatemia was defined as 2 consecutive levels >or=1.5 but or=2 risk factors, with 11% having >4 risk factors. The median entry venous lactate level was 1.2 mmol/L (range: 0.7-5.1 mmol/L). Two subjects had a lactate level >1.5 times the ULN: 1 with a value of 2.1 times the ULN at entry and a week 2 level of 1.2 times the ULN and a second subject with a week 2 value of 1.9 times the ULN but an entry level of 1.4 times the ULN. The latter subject developed symptomatic lactic acidosis 3 weeks following study discontinuation. CONCLUSIONS: Sustained asymptomatic hyperlactatemia among subjects with risk factors associated with hyperlactatemia was not observed when venous lactate was measured in a standardized fashion. One case of hyperlactatemia that evolved into symptomatic lactic acidosis was diagnosed soon after the completion of the study, however. Our findings indicate that asymptomatic hyperlactatemia is either very rare or an artifact of collection technique.     

Hepatic Hodgkin's disease simulating cholestatic hepatitis with liver failure

Fulminant liver failure is an unusual complication that may be seen in patients with hepatic infiltration by non-Hodgkin's lymphomas and leukemias. In such cases, hepatomegaly, marked abnormalities of serum liver function tests, and lactic acidosis may simulate severe viral, alcoholic, or drug hepatitis. We describe the clinical presentation of severe cholestatic hepatitis with liver failure in a patient who was found to have widespread liver involvement by Hodgkin's disease at autopsy. The major histologic findings included extensive portal and periportal Hodgkin's infiltrates, associated loss of periportal liver cells, and variable damage to small bile ducts.     

Inhibition of inotropic effect of hyperosmotic mannitol by lactate in vitro.

Isolated, isometrically contracting cat papillary muscles were used to evaluate the inotropic interactions of lactic acidosis, hypercarbic acidosis, and lactate ion with hypertonic mannitol. These studies have documented that both lactic acidosis (pH less than 7.0) and lactate ion at a normal pH inhibit the inotropic effect of hyperosmotic mannitol in vitro. In contrast, hypercarbic acidosis does not prevent the inotropic effect of mannitol. Inhibition by lactic acid of mannitol's effects on contractility persists in the presence of beta-receptor blockade. The results suggest that inhibition by severe lactic acidosis of the direct inotropic effect of hyperosmolality in isolated cardiac muscle is mediated by lactate ion rather than acidosis per se.     

Lactic acidosis and status asthmaticus: how common in pediatrics?

BACKGROUND: Lactic acidosis is a well described phenomenon in adult patients with severe asthma. However, this entity is rarely reported in children with status asthmaticus. OBJECTIVE: To report our experience in a 13-year-old girl who developed lactic acidosis as a complication of status asthmaticus and to investigate the prevalence of this complication of severe asthma. We sought to determine the frequency of lactic acidosis in such patients and to review etiologies of lactic acidosis. METHODS: 1) Observations on the clinical and laboratory findings in an adolescent girl with status asthmaticus who developed lactic acidosis were recorded. 2) The medical records of 100 children and adolescents with status asthmaticus admitted to an intensive care unit were reviewed for laboratory evidence of lactic acidosis. 3) We also reviewed our own previous experience of status asthmaticus with respiratory failure. RESULTS: Among 100 patients admitted to a pediatric intensive care unit for status asthmaticus, a single case of isolated metabolic acidosis was identified. This proved to be attributable to lactic acidosis. When records of patients with severe respiratory failure were examined, no cases of metabolic acidosis were found. CONCLUSIONS: Although rare, lactic acidosis does occur in pediatric-aged patients during status asthmaticus. It is important that this complication be recognized and treated because acidosis may inhibit the effectiveness of bronchodilator therapy, produce electrolyte disturbances, and cause serious adverse effects on the patient's cardiovascular system.     

Treatment of lactic acidosis with dichloroacetate

We administered dichloroacetate, which prevents or reverses hyperlactatemia in animals and lowers plasma lactate levels in human beings, to 13 patients with lactic acidosis of various causes. All had hypotension, and their acidemia had resisted treatment with sodium bicarbonate. The metabolic effects of dichloroacetate were evaluated in 11 patients. In seven dichloroacetate significantly reduced the level of arterial blood lactate (P less than 0.005) from the base-line value and raised the levels of arterial blood bicarbonate (P less than 0.02) and arterial pH (P less than 0.005). In six of these seven, the acidemia resolved completely with therapy. In 10 of the 13 patients systolic blood pressure increased by 10 to 40 mm Hg, and 4 patients had a 21 per cent increase in cardiac output (P less than 0.02). Despite improvement in their lactic acidemia, all patients but one died of their underlying disease. No serious drug-related toxicity occurred. We conclude that dichloroacetate is a safe and effective adjunct in the treatment of patients with lactic acidosis, although the ultimate prognosis may depend on the underlying disease.     

The acidosis of cholera. Contributions of hyperproteinemia, lactic acidemia, and hyperphosphatemia to an increased serum anion gap

To study the metabolic acidosis that occurs during the diarrhea of cholera, we examined the serum anion gap in 21 patients with hypovolemic shock due to Vibrio cholerae infection. Measurements of serum electrolytes, as well as divalent cations and the anionic contributions of serum proteins, lactate, phosphate, and serum creatinine, were made at the time of admission, after rehydration, and during convalescence. At the time of admission, the mean serum concentration of sodium was 134.8 mmol (meq) per liter, that of chloride was 103.2 mmol per liter, and that of bicarbonate was 11.4 mmol per liter; the mean anion gap was 20.2 mmol per liter. The mean serum creatinine concentration was 2.48 mg per deciliter. The low serum bicarbonate level and the high serum anion gap were corrected by rehydration. The increased serum anion gap was caused by hyperproteinemia, lactic acidemia, and hyperphosphatemia, with anionic contributions to the rise in anion gap estimated as protein, 5.5 meq per liter; lactate, 2.5 meq per liter; and phosphate, 2.5 meq per liter. The hyperproteinemia was attributed to dehydration, the lactic acidemia to shock, and the hyperphosphatemia to acidosis and transient renal failure. The mean concentrations of serum calcium and magnesium were slightly elevated but did not affect the increased anion gap. These results indicate that severe cholera causes acidosis with relatively little change in serum chloride but an increased serum anion gap. The acidosis is more profound than would be expected on the basis of stool losses of bicarbonate, because of superimposed lactic acidemia and renal failure.     

A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group.

BACKGROUND. Mortality is very high in lactic acidosis, and there is no satisfactory treatment other than treatment of the underlying cause. Uncontrolled studies have suggested that dichloroacetate, which stimulates the oxidation of lactate to acetyl-coenzyme A and carbon dioxide, might reduce morbidity and improve survival among patients with this condition. METHODS. We conducted a placebo-controlled, randomized trial of intravenous sodium dichloroacetate therapy in 252 patients with lactic acidosis; 126 were assigned to receive dichloroacetate and 126 to receive placebo. The entry criteria included an arterial-blood lactate concentration of > or = 5.0 mmol per liter and either an arterial-blood pH of < or = 7.35 or a base deficit of > or = 6 mmol per liter. The mean (+/- SD) arterial-blood lactate concentrations before treatment were 11.6 +/- 7.0 mmol per liter in the dichloroacetate-treated patients and 10.4 +/- 5.5 mmol per liter in the placebo group, and the mean initial arterial-blood pH values were 7.24 +/- 0.12 and 7.24 +/- 0.13, respectively. Eighty-six percent of the patients required mechanical ventilation, and 74 percent required pressor agents, inotropic drugs, or both because of hypotension. RESULTS. The arterial-blood lactate concentration decreased 20 percent or more in 83 (66 percent) of the 126 patients who received dichloroacetate and 45 (36 percent) of the 126 patients who received placebo (P = 0.001). The arterial-blood pH also increased more in the dichloroacetate-treated patients (P = 0.005). The absolute magnitude of the differences was small, however, and they were not associated with improvement in hemodynamics or survival. Only 12 percent of the dichloroacetate-treated patients and 17 percent of the placebo patients survived to be discharged from the hospital. CONCLUSIONS. Dichloroacetate treatment of patients with severe lactic acidosis results in statistically significant but clinically unimportant changes in arterial-blood lactate concentrations and pH and fails to alter either hemodynamics or survival.     

Steatosis in donor and transplant liver biopsies

The purpose of this study was to identify the significance and clinical correlation of steatosis in donor and posttransplantation liver biopsies. One hundred twenty-six liver biopsies with fatty change from 86 liver transplant patients were reviewed. Micro- and macro-steatosis were graded semiquantitatively and correlated with clinical and other pathologic parameters. Fifty-one donor biopsy specimens, from 50 patients, had combinations of micro- (predominantly) and macro-steatosis. One of 2 patients with high-grade micro- and macro-steatosis required a retransplantation on the third day. Three early deaths were not related to graft dysfunction. In 36 patients, steatosis developed after transplantation. In 13 of 36, steatosis was seen in the early postoperative period with a background of severe ischemic injury, 6 of whom died within 45 days posttransplantation. Other causes of steatosis developing after liver transplantation included hepatitis C (n = 12), alcoholic steatohepatitis (n = 3), diabetes mellitus or obesity (n = 7) and poor nutrition (n = 2). The presence of steatosis in 1 patient's donor and all posttransplantation biopsy specimens remained unexplained. In conclusion, (1) microsteatosis in donor liver biopsy specimens has no effect on graft function; (2) ischemic injury with development of steatosis in the early posttransplantation period may be associated with poor clinical outcome; and (3) steatosis in the posttransplantation period is uncommon and usually related to recurrent or acquired hepatitis C.