[Show abstract][Hide abstract] ABSTRACT: Antibacterial and antifungal agents are among the most frequently prescribed medications, yet clinically significant liver injury is a relatively rare event. In addition, assessment of the hepatotoxicity of antibacterial and antifungal agents is confounded by the effects and severity of the underlying infection being treated. Nevertheless, antibiotics are the most common agents implicated in drug-induced liver injury. There are well-described hepatic reactions to antibacterial and antifungal agents, the majority of which are idiosyncratic. Prompt recognition of antibiotic-associated liver injury is critical, since recovery with discontinuation of the offending agent is the norm, although notable exceptions include vanishing bile duct syndrome associated with amoxicillin-clavulanic acid, severe acute hepatitis from trovafloxacin use, minocycline-associated autoimmune hepatitis, and chronic liver disease from the prolonged use of nitrofurantoin. Prompt recognition, discontinuation of the drug and substitution, if clinically indicated, with an alternative agent, and avoidance of rechallenge are the most effective means of managing suspected hepatotoxicity from antibacterial and antifungal agents.
[Show abstract][Hide abstract] ABSTRACT: A 55-year-old man presented with sinus congestion, headaches, chills, mild nausea, fatigue, and a "foggy" sensation that had lasted approximately 1 week. He reported darker urine than usual and had noticed that his eyes were turning yellow.
New England Journal of Medicine 10/2012; 367(14):1342-7. DOI:10.1056/NEJMcps1011784 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gamma-butyrobetaine (GBB) is a precursor in the biosynthesis of carnitine, which plays an important role in the beta-oxidation of fatty acids, and is converted to carnitine by gamma-butyrobetaine dioxygenase (BBD) predominantly in liver. We investigated the molecular mechanism of hepatic uptake of GBB in rat hepatocytes. Cellular localization of rat Octn2 (rOctn2:Slc22A5) was studied by Western blot analysis. Uptake of deuterated GBB (d(3)-GBB) was examined in HEK293 cells expressing rOctn2 (HEK293/rOctn2) and freshly isolated rat hepatocytes. d(3)-GBB was quantified by use of liquid chromatography-tandem mass spectrometry. Western blot analysis demonstrated an expression of OCTN2 protein in hepatic basolateral membrane but not in bile canalicular membrane fraction. Furthermore, we found that d(3)-GBB was taken up by rOctn2 in an Na(+)-dependent manner with K(m) value of 13 microM. The apparent K(m) value for d(3)-GBB transport in freshly isolated rat hepatocytes was 9 microM. d(3)-GBB uptake by the rat hepatocytes was inhibited by gamma-aminobutyric acid (GABA) to 30% of the control, whereas it was inhibited by carnitine to 62% of the control, even at 500 microM. Furthermore, d(3)-GBB uptake by rat hepatocytes was decreased by 45% with rat Gat2 (Slc6A13, a major liver GABA transporter) silenced by the microRNA method. Accordingly, the present study clearly demonstrates that GBB is taken up by hepatocytes for carnitine biosynthesis not only via Octn2 but also via the GABA transporter, possibly Gat2.
[Show abstract][Hide abstract] ABSTRACT: Diets high in trans fats are associated with an increased risk of cardiovascular disease and components of the metabolic syndrome. The influence of these toxic fatty acids on the development of nonalcoholic fatty liver disease has not been significantly examined. Therefore, we sought to compare the effect of a murine diet high in trans fat to a standard high-fat diet that is devoid of trans fats but high in saturated fats. Male AKR/J mice were fed a calorically identical trans fat diet or standard high-fat diet for 10 days, 4 wk, and 8 wk. Serum alanine aminotransferase (ALT), lipid, insulin, and leptin levels were determined and the quantitative insulin-sensitivity check index (QUICKI) was calculated as a measure of insulin resistance. Additionally, hepatic triglyceride content and gene expression of several proinflammatory genes were assessed. By 8 wk, trans fat-fed mice exhibited higher ALT values than standard high-fat-fed mice (126 +/- 16 vs. 71 +/- 7 U/l, P < 0.02) despite similar hepatic triglyceride content at each time point. Trans fat-fed mice also had increased insulin resistance compared with high-fat-fed mice at 4 and 8 wk with significantly higher insulin levels and lower QUICKI values. Additionally, hepatic interleukin-1beta (IL-1beta) gene expression was 3.6-fold higher at 4 wk (P < 0.05) and 5-fold higher at 8 wk (P < 0.05) in trans fat-fed mice compared with standard high-fat-fed mice. Trans fat feeding results in higher ALT values, increased insulin resistance, and elevated IL-1beta levels compared with standard high-fat feeding.
[Show abstract][Hide abstract] ABSTRACT: The thiazolidinedione derivatives, troglitazone, rosiglitazone, and pioglitazone, are novel insulin-sensitizing drugs that are useful in the treatment of type 2 diabetes. However, hepatotoxicity associated with troglitazone led to its withdrawal from the market in March 2000. In view of case reports of hepatotoxicity from rosiglitazone and pioglitazone, it is unclear whether thiazolidinediones as a class are associated with hepatotoxicity. Although the mechanism of troglitazone-associated hepatotoxicity has not been elucidated, troglitazone and its major metabolite, troglitazone sulfate, competitively inhibit adenosine triphosphate (ATP)-dependent taurocholate transport in isolated rat canalicular liver plasma membrane vesicles mediated by the canalicular bile salt export pump (Bsep). These results suggest that cholestasis may be a factor in troglitazone-associated hepatotoxicity. To determine whether this effect is 1) limited to canalicular bile acid transport and 2) is specific to troglitazone, the effect of troglitazone, rosiglitazone, and ciglitazone on bile acid transport was examined in rat basolateral (blLPM) and canalicular (cLPM) liver plasma membrane vesicles. In cLPM vesicles, troglitazone, rosiglitazone, and ciglitazone (100 microM) all significantly inhibited ATP-dependent taurocholate transport. In blLPM vesicles, these three thiazolidinediones also significantly inhibited Na(+)-dependent taurocholate transport. Inhibition of bile acid transport was concentration dependent and competitive in both cLPM and blLPM vesicles. In conclusion, these findings are consistent with a class effect by thiazolidinediones on hepatic bile acid transport. If hepatotoxicity is associated with this effect, then hepatotoxicity is not limited to troglitazone. Alternatively, if hepatotoxicity is limited to troglitazone, other mechanisms are responsible for its reported hepatotoxicity.
Life Sciences 02/2007; 80(8):732-40. DOI:10.1016/j.lfs.2006.11.001 · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 2002 marked the first time that the rate of hospital spending in the United States out-paced the overall health care spending rate of growth since 1991. As hospital spending continues to grow and as reimbursement for hospital expenses has moved towards the prospective payment system, there is still increasing pressure to reduce costs. Hospitals have a major incentive to decrease resource utilization, including hospital length of stay. We evaluated whether physician profiling affects physician satisfaction and hospital length of stay, and assessed physicians' views concerning hospital cost containment and the quality of care they provide.
To determine if physician profiling affects hospital length of stay and/or physician satisfaction, we used quasi-experimental with before-versus-after and intervention-versus-control comparisons of length of stay data collected at an intervention and six control hospitals. Intervention hospital physicians were informed their length of stay would be compared to their peers and were given a questionnaire assessing their experience.
Nearly half of attending pre-profiled physicians felt negative about the possibility of being profiled, while less than one-third of profiled physicians reported feeling negative about having been profiled. Nearly all physicians greatly enjoyed their ward month. Length of stay at the profiled site decreased by an additional 1/3 of a day in the profiling year, compared to the non-profiled sites (p < 0.001).
A relatively non-instrusive profiling intervention modestly reduced length of stay without adversely affecting physician satisfaction.
BMC Health Services Research 04/2006; 6(1):45. DOI:10.1186/1472-6963-6-45 · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 46-year-old Mexican immigrant presented with epigastric pain and vomiting of coffee-grounds material. He reported fatigue, malaise, jaundice, and a weight loss of 20 lb (9.1 kg) during the previous two months. He had also had dark stools, light-headedness, and mild shortness of breath, but no fever, chills, or night sweats.
New England Journal of Medicine 02/2006; 354(5):509-514. DOI:10.1056/NEJMcps051762 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We describe a 52-year-old man with type 2 diabetes mellitus who developed cholestatic hepatitis in association with rosiglitazone use. Liver biopsy findings included dilated canaliculi, inspissated bile, intrahepatocellular bile pigment deposits, and enlarged xanthomatous Kupffer cells. The form of liver injury reported in this case differs markedly from those reported previously for rosiglitazone.
[Show abstract][Hide abstract] ABSTRACT: Sahai A, Malladi P, Melin-Aldana H, Green RM, Whitington PF. Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol Gastrointest Liver Physiol 2004;287:G264-G273. (Reprinted with permission of American Physiological Society)
The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-α, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1-4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-α expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-β and TNF-α. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN-/- mice when compared to OPN+/+ mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH.
Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 2004;113:1774-1783. (Reproduced with permission of the Journal of Clinical Investigation.)
PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation of Pten in mice (AlbCrePtenflox/flox mice). AlbCrePtenflox/flox mice showed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, implying adipogenic-like transformation of these cells. Genes involved in lipogenesis and β-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARγ and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePtenflox/flox livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCrePtenflox/flox livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePtenflox/flox mice also showed insulin hypersensitivity. In vitro, AlbCrePtenflox/flox hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.
[Show abstract][Hide abstract] ABSTRACT: Sepsis-associated cholestasis should always be considered as part of the differential diagnosis of jaundice in the hospitalized or critically ill patient. The development of a disproportionate elevation of serum bilirubin in comparison with serum alkaline phosphatase and serum aminotransferases should be considered an early warning sign of an underlying infection, even in the absence of fever,leukocytosis, or other signs or symptoms. Prompt recognition and appropriate medical and surgical intervention may reduce morbidity and mortality.
[Show abstract][Hide abstract] ABSTRACT: The incidence of acute liver failure or serious liver injury in diabetic patients is needed to evaluate the safety of hypoglycemic drug therapy.
We conducted a retrospective cohort study of 5 health maintenance organizations. Study patients were 171,264 health plan members 19 years or older when they received oral hypoglycemic drugs or insulin between April 1, 1997, and June 30, 1999. We searched for hospital discharge diagnoses and procedures potentially indicative of acute liver injury and reviewed the full-text medical records. Acute liver failure was defined as acute liver disease and (1) hepatic encephalopathy, (2) prothrombin time prolongation greater than 3 seconds or international normalized ratio greater than 1.5, and (3) a total bilirubin level greater than 3.0 mg/dL (>51 micro mol/L). Acute liver injury was diagnosed in individuals who did not meet 1 or more of the criteria for acute liver failure but had alanine transaminase or aspartate transaminase levels greater than 500 U/L.
We identified 35 cases of acute liver failure or injury not clearly attributable to a known cause other than use of hypoglycemic agents. The age- and sex-standardized incidence per 1000 person-years was 0.15 for insulin users, 0.08 for sulfonylurea users, 0.12 for metformin users, and 0.10 for troglitazone users. The incidence was higher (on the order of 0.3 per 1000) during the first 6 months of exposure to all hypoglycemic agents.
Acute liver failure or injury not clearly attributable to other known causes occurred on the order of 1 per 10,000 person-years among diabetic patients treated with oral hypoglycemic drugs or insulin.
Archives of Internal Medicine 03/2003; 163(6):728-34. DOI:10.1001/archinte.163.6.728 · 17.33 Impact Factor