Keith G. Tolman

The liver and lovastatin.

Abstract The cholesterol-lowering agents, known as statins, have been in use for 15 years and are among the most commonly prescribed drugs. Animal studies and premarketing clinical trials have given signals of hepatotoxicity, primarily minor elevations in serum alanine aminotransferase enzyme (ALT) levels. For that reason, all of the cholesterol-lowering drugs have labeling that requires monitoring of liver enzymes. Postmarketing experience, however, suggests that hepatotoxicity is rare and thus it is timely to revisit the issue. The first of the statins, lovastatin, was approved in 1986 and has acquired 24 million patient-years of clinical experience. Minor elevations in liver enzymes, i.e., ALT 3 × the upper limit of normal (ULN) occur in 2.6% and 5.0% of patients on lovastatin doses of 20 and 80 mg/day, respectively. These elevations are reversible with continuing therapy, are dose related, and are probably related to cholesterol lowering per se. Rare cases of acute liver failure (ALF) have been reported with all of the cholesterol-lowering drugs. With lovastatin, the rate is approximately 1/1.14 million patient-treatment years, which is 9% of the background rate of all causes of ALF and approximately equal to the background rate of idiopathic ALF. Monitoring for hepatotoxicity has not been effective in preventing serious liver disease, largely because of its rarity and the poor predictive value of minor ALT elevations. In fact, it may increase patient risk because of needless discontinuation of cholesterol-lowering therapy for false-positive results in patients who are benefiting from treatment.

Narrative Review: Hepatobiliary Disease in Type 2 Diabetes Mellitus

Diabetes mellitus is the fifth leading cause of death in the United States; an estimated 17 million people are affected (1). Of these, 90% have type 2 diabetes. Many, however, are unaware that they have the disease, and thus the number of people actually affected is probably much greater (2). Only recently has liver disease been recognized as a major complication of type 2 diabetes. The standardized mortality ratio (that is, the relative risk compared to the background population) for death due to cirrhosis is greater than for cardiovascular disease (3). In this review, we discuss the spectrum of liver disease in type 2 diabetes, including nonalcoholic fatty liver disease, cirrhosis, hepatocellular carcinoma, hepatitis C, acute liver failure, and cholelithiasis. In addition, we review the metabolic effects of type 2 diabetes on the liver, the hepatotoxicity of antihyperglycemic medications, and the treatment of diabetes in patients with liver disease. Methods We searched MEDLINE for the primary literature using Medical Subject Heading and free-text terms. The search also included the bibliographies of each citation for relevant articles. When full-text articles were unavailable, we included abstracts in the search. The U.S. Food and Drug Administration (FDA) Web site was also searched for reports of hepatotoxicity. The Metabolic Effects of Type 2 Diabetes on the Liver Carbohydrate and lipid metabolism are affected by the insulin resistance and relative insulin deficiency in type 2 diabetes. Insulin resistance decreases glucose uptake in skeletal muscle and increases adipocyte lipolysis. The lipolysis results in increased circulating plasma free fatty acids, which, in turn, may lead to more insulin resistance. In effect, a vicious cycle is started. Alternatively, the elevated plasma free fatty acids, which occur secondary to obesity, may induce peripheral insulin resistance. Whatever the mechanism, the net effect is increased storage of fat in the liver (Figure 1). Figure 1. Some metabolic effects of insulin resistance in skeletal muscle, fat, and liver. Carbohydrate Metabolism The elevated plasma free fatty acid level resulting from insulin resistance negatively affects glucose homeostasis by increasing hepatic glucose production and decreasing peripheral clearance (4, 5). Under physiologic conditions, compensatory hyperinsulinemia would suppress hepatic gluconeogenesis and glycogenolysis, thus restoring glucose homeostasis. Patients with type 2 diabetes, however, are resistant to these suppressive effects of insulin (6). The elevated free fatty acid level does not increase plasma insulin levels sufficiently to overcome the hepatic and peripheral effects of insulin resistance (7). In this way, reduced glucose utilization leads to hyperglycemia, which, in turn, contributes to the vascular complications of diabetes. Lipid Metabolism Patients with type 2 diabetes frequently have dyslipidemia characterized by elevated plasma triglyceride levels; reduced high-density lipoprotein cholesterol levels; and a predominance of small dense low-density lipoprotein particles, a pattern frequently seen in nonalcoholic fatty liver disease (8). The major cause of hypertriglyceridemia is hepatic overproduction of triglyceride-rich very-low-density lipoprotein (VLDL) and apolipoprotein B (apoB) caused by hyperinsulinemia and the increased availability of free fatty acid substrate (9, 10). In healthy humans, insulin decreases VLDL-1 apoB release. However, patients with type 2 diabetes do not adequately suppress hepatic VLDL-1 apoB production, which leads to hypertriglyceridemia (10). Decreased lipoprotein lipase activity in fat and skeletal muscle contributes to the reduced clearance of triglyceride-rich lipoproteins (8, 11, 12). Hepatobiliary Disorders Associated with Diabetes Hepatobiliary disorders occur more frequently in patients with type 2 diabetes. These disorders include nonalcoholic fatty liver disease, cirrhosis, hepatocellular carcinoma, hepatitis C, acute liver failure, and cholelithiasis. Nonalcoholic Fatty Liver Disease Nonalcoholic fatty liver disease refers to a broad spectrum of liver disease ranging from steatosis (bland fatty infiltration of hepatocytes) to nonalcoholic steatohepatitis (steatosis plus inflammation, necrosis, or fibrosis) to cirrhosis and, in some patients, to end-stage liver disease and hepatocellular carcinoma. Nonalcoholic fatty liver disease resembles alcoholic liver disease (13). Its prevalence is as high as 50% in patients with type 2 diabetes and 100% in patients with diabetes and obesity. Of these affected patients, 50% have steatohepatitis and 19% have cirrhosis (14-16). Nonalcoholic fatty liver disease (from all causes) is the most prevalent liver disease in the United States (17). The pathogenesis of nonalcoholic fatty liver disease is partially understood. Steatosis reflects the net retention of lipids within hepatocytes. This results from an imbalance between the uptake and synthesis of fatty acids and their oxidation and export. Angulo (18) has described these mechanisms in detail. The most consistent pathogenic factor is insulin resistance, leading to enhanced lipolysis, which, in turn, increases circulating free fatty acids (14). The increase in fatty acids overloads the mitochondrial -oxidation system, and fatty acids accumulate in the liver. Fatty acids induce the cytochrome P450 4A and 2E1 isoenzymeslipoxygenases that can generate free oxygen radicals (19). Reactive oxygen species promote disease progression by both lipid peroxidation and cytokine induction (20). Lipid peroxidation leads to the release of malondialdehyde and 4-hydroxynonenal. These substances cause cell death and protein cross-linkage, resulting in the formation of Mallorys hyaline in the hepatocyte (21). They also activate stellate cells, which leads to collagen synthesis and fibrosis (22). Cytokine induction promotes inflammation (23). Taken together, these are the characteristic histologic features of nonalcoholic fatty liver disease. The diagnosis of nonalcoholic fatty liver disease is suspected in patients who do not use alcohol and have mildly elevated aminotransferase levels. The clinical features are nondescript. Most patients do not have signs or symptoms of liver disease; however, some report malaise or a sense of fullness in the right upper quadrant. Hepatomegaly may be present. Laboratory studies reveal mild elevations of alanine aminotransferase (ALT) and aspartate aminotransferase levels. Serum alkaline phosphatase and -glutamyltransferase levels may be mildly elevated. Serum ferritin levels are elevated in almost half of the patients (24, 25). The hepatic iron index and iron level, however, are usually normal. Indicators of more advanced disease include a ratio of aspartate to alanine aminotransferase greater than 1 and higher levels of plasma triglycerides (24). Iron overload may be associated with increased severity of disease (26), but this remains controversial (24, 27, 28). Imaging studies are helpful in diagnosing steatosis. The disorder appears as a diffuse increase in echogenicity (so-called bright liver) on ultrasonography, which has a sensitivity of 89% and a specificity of 93% for detecting steatosis (Figure 2, top)(29). Areas of focal fat-sparing appear as masses (so-called phantom tumor) (Figure 2, bottom) (30). Magnetic resonance spectroscopy allows quantitative assessment of steatosis (31). However, only liver biopsy can assess the severity of damage and the prognosis. Figure 2. Ultrasonographic findings from a patient with steatosis. Top. Bottom. The histologic features of steatohepatitis, which include steatosis, inflammation, ballooning hepatocyte necrosis, Mallorys hyaline, and fibrosis, are indistinguishable from those of alcoholic liver disease (Figure 3). As the disease advances toward cirrhosis, the steatosis and necroinflammatory response recede (27). The natural history of nonalcoholic fatty liver disease from steatosis to steatohepatitis to cirrhosis and, finally, to hepatocellular carcinoma is well established (25, 32); however, it is not known why some patients progress while others do not. The prognosis worsens with each stage of progression. In one study, 36% of all patients died after a mean follow-up period of 8.3 years (27). Figure 3. Liver biopsy specimens from persons with steatohepatitis. Top. Bottom. Treatment of fatty liver consists of good metabolic control and weight reduction. Weight loss improves insulin sensitivity and usually results in reduction of steatosis (33-37), but the necroinflammation and fibrosis may worsen if the weight reduction is rapid (33, 38, 39). This paradoxical effect may be caused by increased circulating free fatty acids from the increased lipolysis seen with fasting. The most effective rate of weight loss is not known, but approximately 1.5 kg per week has been recommended (33). The content of the diet is a matter of debate. Given that saturated fatty acids increase insulin resistance, a diet enriched with unsaturated fatty acids is theoretically reasonable. Pharmacologic therapy with gemfibrozil (40), vitamin E (41), metformin (42, 43) ursodeoxycholic acid (44-46), betaine (47), pioglitazone (48-51), rosiglitazone (52), and atorvastatin (53, 54) has been investigated. Angulo (55) recently reviewed these therapies. All have been shown to improve liver enzyme levels. Betaine, vitamin E, and troglitazone (subsequently withdrawn from the market) led to modest histologic improvement. One prospective controlled study with ursodeoxycholic acid and diet showed improvement or normalization in liver enzyme levels (45). Another prospective controlled study of 166 patients did not show histologic improvement after 2 years (46). Given that insulin resistance is the most consistent feature of fatty liver disease, it is reasonable to use insulin-sensitizing agents. A 6-month study with pioglitazone and vitamin E showed histologic improvement

Hepatotoxicity of the thiazolidinediones

Troglitazone, the first of the thiazolidinediones, caused severe hepatotoxicity including liver failure in several patients. It appears, however, that the thiazolidinediones as a class are not as hepatotoxic as troglitazone. Comparative data at comparable dates of usage indicate that pioglitazone and rosiglitazone are not significant hepatotoxins. This is further supported by experimental data that demonstrate that troglitazone, alone among the thiazolidinediones, is toxic in hepatocyte cell culture. All of the thiazolidinediones cause ALT elevations; however, ALT monitoring for hepatotoxicity does not appear to prevent serious liver disease nor reduce patient risk.

Defining patient risks from expanded preventive therapies.

In clinical trials, all lipid-lowering agents have been associated with mild, asymptomatic elevations of alanine aminotransferase (ALT) and asparate aminotransferase enzymes. This, along with the fact that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are hepatotoxic in some animals, led the US Food and Drug Administration (FDA) to recommend monitoring of liver enzymes for all lipid-lowering agents, except the bile acid sequestrants. Because the drugs act by different mechanisms, ALT elevations may be a pharmacodynamic effect related to lipid lowering, rather than a direct effect of the drug. Animal studies support this assumption. ALT elevations of 3 times the upper limit of normal occur in <3% of patients in clinical trials of lipid-lowering drugs. The elevations are transient and often dose-related, and they usually revert to normal while continuing therapy and have never been associated with hepatotoxicity. Confounding factors include alcohol, acetaminophen, and pre-existing liver disease, such as chronic hepatitis C and type II diabetes with fatty liver, which are both associated with mild, intermittent elevations of ALT. The more important issue is whether or not lipid-lowering agents are hepatotoxic. There are case reports of hepatotoxicity (cholestasis, jaundice, hepatitis, chronic active hepatitis, fatty liver, cirrhosis and acute liver failure) with all of the drugs, except cholestyramine. To date there are just 5 cases of documented liver failure linked to lovastatin. There is no evidence that monitoring reduces the rate of hepatotoxicity. Mild elevations of ALT that occur with many drugs, including HMG-CoA reductase inhibitors, do not predict hepatotoxicity. Liver enzyme elevations appear to be a class characteristic of lipid-lowering agents. Hepatotoxicity is a rare idiosyncratic reaction, occurring only with sustained released nicotinic acid.

Chronic Liver Disease and Acetaminophen

A 59-year-old female patient with arthritis developed liver function abnormalities while taking therapeutic doses of acetaminophen. Liver biopsy showed evidence of acute and chronic liver damage. Rechallenge with acetaminophen induced abnormal liver functions almost immediately. The patient has been followed for 2 years since that challenge and remains asymptomatic. Biochemical tests of liver function have returned to normal.

Hepatotoxicity of non-narcotic analgesics

The central role of the liver in drug metabolism sets the stage for drug-related hepatotoxicity. The incidence of hepatotoxicity associated with non-narcotic analgesics is low, but their widespread use both prescription and over-the-counter-makes analgesic-associated hepatotoxicity a clinically and economically important problem. Hepatotoxicity is considered a class characteristic of nonsteroidal anti-inflammatory drugs (NSAIDs), despite the fact that they are a widely diverse group of chemicals. In fact, there are many differences in the incidence, histologic pattern, and mechanisms of hepatotoxicity between, as well as within, chemical classes. Most NSAID reactions are hepatocellular and occur because of individual patient susceptibility (idiosyncrasy). Aspirin, however, is a dose-related intrinsic hepatotoxin. Acetaminophen is also an intrinsic hepatotoxin but rarely demonstrates hepatotoxicity at therapeutic doses. It does cause hepatotoxicity with massive overdoses and with therapeutic doses in susceptible patients such as chronic users of alcohol. No hepatotoxicity has been reported to date with tramadol, another non-narcotic analgesic.

The Toxicity of Metabolites of Sodium Valproate in Cultured Hepatocytes

Abstract: Sodium valproate is hepatotoxic in both humans and rat hepatocytes. The toxicity is dose related and frequently associated with simultaneous ingestion of drugs which induce the drug metabolizing system. For these reasons, metabolites of sodium valproate were tested for toxicity using rat hepatocyte cultures. The sodium salts of three metabolites, 2‐propylpent‐4‐enoate, 4‐hydroxyvalproate, and perhaps 5‐hydroxyvalproate, were toxic in this system. In addition, 2‐propylpent‐4‐enoate was toxic in a dose‐related fashion. All are ω and ω‐1 oxidation products in the microsome‐mediated pathway of valproate metabolism.

Enhanced transdermal delivery of testosterone : a new physiological approach for androgen replacement in hypogonadal men

Abstract This report describes the rationale, development and initial clinical testing of a new modality for the treatment of hypogonadal men — an enhanced transdermal delivery system (TDS) for administering native testosterone. In contrast to the experimental trans-scrotal testosterone patches, the enhanced testosterone TDS can be applied to non-scrotal skin sites, such as the back, chest, arms, etc. A one-month pilot study in six hypogonadal men shows that the nightly application of two patches (for 24 h) delivers ~ 4 to 7 mg of testosterone per day, and produces testosterone plasma levels that closely mimic the magnitude and time course of the normal circadian rhythm seen in healthy young men. Moreover, the enhanced delivery of testosterone across non-scrotal skin, is not associated with any appreciable degree of transdermal first-pass metabolism, and therefore produces physiological levels and patterns of dihydrotestosterone (DHT) and estradiol (E 2 ). In all but one subject, skin tolerability has been acceptable. During 7 months of treatment in two patients, hormone levels have remained within the normal range, tolerability has been good, and subjective improvements in sexual function and well being have been reported. In comparison to other available methods of androgen replacement therapy (i.e. testosterone-ester injections, synthetic oral agents and testosterone pellet implants), we believe that the enhanced transdermal delivery of native testosterone promises to be a more physiological and patient-friendly approach for the treatment of hypogonadal men.

Chemical Structure of Erythromycin and Hepatotoxicity

Abstract The biochemical features of erythromycin estolate essential for hepatotoxicity were studied in a patient with proved erythromycin estolate toxicity. The only two variables in commercial er...

The safety of thiazolidinediones.

Introduction: The prevalence of type 2 diabetes mellitus (T2DM) has reached epidemic proportions. Many new therapies have emerged, including thiazolidinediones (TZDs), selective agonists of PPAR-γ, now used as both primary and add-on therapies. Given that T2DM is a lifetime disease, there is a need for assurance that new drugs are both safe and effective. Recent concern about the cardiovascular safety of one of the new drugs, rosiglitazone, is the stimulus for this review. Areas covered: The safety of pioglitazone and rosiglitazone under the headings of liver safety, cardiovascular safety, fluid retention, weight gain and bone fractures is reviewed based on a PubMed search of the years 1997 through June 2010. This review also describes the magnitude of the risks of the TZDs and provides a recommendation on the use of TZDs. Expert opinion: Liver safety is no longer an issue with the TZDs. There are no significant differences between rosiglitazone and pioglitazone in fluid retention, weight gain and bone fractures. However, pioglitazone tends to be cardioprotective while rosiglitazone is cardiotoxic. There is no current justification for prescribing rosiglitazone.