Nonalcoholic steatohepatitis: what we know in the new millennium

Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by diffuse fatty infiltration and inflammation. The exact prevalence of NASH is unclear, but it is becoming more evident that the disease is much more common than previously thought. Although generally a benign, indolent process, it can progress to advanced liver disease in approximately 15-20% of patients. Clinical characteristics associated with NASH include obesity, hyperlipidemia, diabetes mellitus, and hypertension, all of which have been associated with underlying insulin resistance. Typically, this disease becomes evident in the fourth or fifth decade of life with an equal sex predilection. NASH is thought to be caused, in part, by impaired insulin signaling, leading to elevated circulating insulin levels and subsequent altered lipid homeostasis. This process is likely multifactorial and includes both genetic and environmental factors. Treatment options to date are limited and are based on very small clinical trials. Current investigations are focusing on improving the underlying insulin resistance that has been associated with NASH as well as other therapies that decrease oxidative stress or improve hepatocyte survival.     

Statins in Nonalcoholic Fatty Liver Disease and Steatohepatitis: Updated Review

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that refers to the presence of hepatic steatosis without significant intake of alcohol. NAFLD is an asymptomatic disease that can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The most common cause of mortality in patients with NAFLD or NASH is cardiovascular disease (CVD). Currently, the treatment of NAFLD focuses on gradual weight loss and life style modifications. However, multifactorial treatment of NAFLD or NASH risk factors may be needed to reduce the likelihood of these patients developing CVD. This review discusses the mechanisms that link hyperlipidemia and NAFLD. In addition, the review focuses on the safety and efficacy of statins in patients with NAFLD or NASH, and their effect on the extent of hepatic steatosis and fibrosis based on human studies.     

NAFLD and Cardiovascular Disease: Can the Real Association Be Determined?

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver diseases ranging from isolated hepatic steatosis (IHS) to non-alcoholic steatohepatitis (NASH) defined by the presence of hepatocellular injury, and may progress to end-stage liver disease and its complications. Mounting evidence also suggests that direct effects on the heart may explain why cardiovascular disease (CVD), comprising coronary artery disease and cerebrovascular disease, is the leading cause of death among individuals with NASH. CVD and NASH share common risk factors, however NASH may increase atherogenic risk or alter cardiac function independent of these commonalities. A complex interplay between an inflamed visceral fat compartment, the liver and the endothelium creates a pro-inflammatory, pro-coagulant and pro-atherogenic milieu that can contribute to accelerated atherosclerosis and cardiac dysfunction. While new evidence is accumulating that might help close the gap in our understanding of the putative role of NASH in CVD, more prospective data are still needed.     

Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients

BACKGROUND/AIMS: Non-alcoholic steatohepatitis (NASH) is a disorder that is histologically characterized by macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and fibrosis. NASH can range from a benign condition to end-stage liver disease. The mechanisms promoting transition from steatosis to NASH appear to involve multiple cellular adaptations to the oxidative stress occurring when fatty acid metabolism is altered. We evaluated the relationship between lipid peroxidation and other oxidative stress biomarkers with changes in expression of heme oxygenase-1 (HO-1) in human hepatic steatosis ranging from simple steatosis to NASH. METHODS: HO-1 expression, lipid peroxidation, ferritin and GSH levels were assayed from liver biopsies obtained from 60 subjects: 35 with NASH, 15 with simple steatosis and 10 controls. RESULTS: The HO-1 expression was significantly increased in NASH patients and the increase reflected the severity of the disease. A significant correlation was observed between the increased levels of HO-1 and ferritin, and between the increased levels of HO-1 and lipid peroxidation. Moreover, NASH patients with lower levels of GSH exhibited higher expression of HO-1. CONCLUSIONS: The induction of HO-1 is an adaptive response against oxidative damage elicited by lipid peroxidation and it may be critical in the progression of the disease.     

Can Nash Be Diagnosed,Graded, and Staged Noninvasively?

Nonalcoholic bland steatosis and nonalcoholic steatohepatitis (NASH) are stages in the spectrum of nonalcoholic fatty liver disease (NAFLD). NASH may progress to end-stage liver disease. Liver biopsy distinguishes between patients with NASH and no NASH and can stage fibrosis. Markers of hepatocyte apoptosis hold promise as noninvasive tests for NASH diagnosis. Several scoring systems that combine routine clinical and laboratory variables and some proprietary panels can assist in predicting fibrosis severity. Noninvasive imaging modalities are reasonably accurate available tools to determine severity of fibrosis in NAFLD, but none of them yet can replace liver biopsy.     

Nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a condition characterized by hepatomegaly, elevated serum aminotransferase levels, and a histologic picture similar to alcoholic hepatitis in the absence of alcohol abuse. Most patients with NASH are obese women, and many have diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia. NASH has also been associated with a number of metabolic conditions, surgical procedures, and drug treatments. Most patients are asymptomatic. The most common sign of NASH is hepatomegaly. Stigmata of chronic liver disease are rare. Laboratory abnormalities include a 2-4-fold elevation of serum aminotransferase levels; other liver function test results are usually normal. Histologically, there is moderate to severe macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and/or fibrosis. The pathogenesis of NASH is poorly understood, but lipid peroxidation and oxidative stress are the leading culprits. The natural history of NASH is unknown, but NASH seems to be a stable disease in most patients. Treatment of NASH is unproven, but weight reduction is recommended in obese patients. Small pilot studies of several drugs have shown promise, but large randomized clinical trials are awaited. Orthotopic liver transplantation is the treatment of choice for end-stage liver disease secondary to NASH.     

Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD)/nonalcoholic steatohepatitis(NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers(thiazolidinediones) and antioxidants(vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.     

Lipid-lowering agents in nonalcoholic fatty liver disease and steatohepatitis: human studies

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease which refers to the presence of hepatic steatosis without significant intake of alcohol. NAFLD is an asymptomatic disease that can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is currently the most common cause of incidental abnormal liver tests and elevated serum liver enzyme activities in the developed world. Obesity, diabetes, and other components of the metabolic syndrome are frequently associated with the NAFLD. The treatment of NAFLD focuses on life-style modifications. Statins, fibrates, and other lipid-lowering agents have been proposed as effective lipid-lowering treatments in patients with NAFLD/NASH. However, clinicians are concerned that hyperlipidemic patients with NAFLD/NASH who are treated with statins could develop transaminitis. We assessed the efficacy and safety of lipid-lowering agents for NAFLD/NASH by reviewing reports of human studies including pilot, prospective, preliminary, and post hoc analysis studies on online databases during the period of 1980 to December 2012. The results of studies provide compelling evidence that lipid-lowering agents are safe and efficacious in patients with NAFLD/NASH and that some of these agents can induce a reduction in the extent of the hepatic steatosis. Well-designed randomized controlled studies of adequate size and duration with histological endpoints are needed in order to establish a suitable lipid-lowering treatment for hyperlipidemic patients with NAFLD/NASH, and for nonhyperlipidemic patients with NAFLD/NASH with a high risk for cardiovascular disease.     

Hepatocellular carcinoma in non‐alcoholic steatohepatitis: Growing evidence of an epidemic?

The incidence of hepatocellular carcinoma in non‐viral‐related chronic liver disease has gradually increased in Japan. Obesity and diabetes mellitus type 2 have been established as a significant risk factor for hepatocellular carcinoma (HCC) by epidemiologic observations and experimental studies. The risks of these factors for HCC are likely conferred by two factors: the increased risk for development of non‐alcoholic steatohepatitis (NASH) and the carcinogenic potential of themselves. Hepatocellular carcinoma in NASH is difficult to evaluate because histological diagnosis is required for diagnosis of NASH, which can lead selection bias. Furthermore, end‐stage NASH is in effect “burned‐out” NASH, for which the diagnosis of NASH cannot be made any more. At all events, previous studies on the etiology of Japanese HCC showed that non‐alcoholic fatty liver disease accounts for 1–5% of all HCC (male predominant, median age 72 years). They have high prevalences of obesity and/or diabetes mellitus type 2 and 10–75% of the HCC arose from non‐cirrhotic livers. HCC in NASH may be of multicentric origin, similar to HCC based on viral hepatitis. Regular screening for HCC is extremely important especially in cirrhotic NASH patients and recurrence should be warned. In western and Asian countries, the prevalence of non‐alcoholic fatty liver disease in the general population is increasing dramatically. Therefore, there is an urgent need to elucidate pathogenesis and clinical features of HCC in NASH. In this review we summarize current concepts for HCC in NASH.     

Mitochondrial abnormalities in non-alcoholic steatohepatitis.

BACKGROUND/AIMS: We assessed mitochondrial morphology by electron microscopy and the prevalence of a mitochondrial gene deletion in patients with non-alcoholic steatohepatitis (NASH), alcohol-related liver disease and non-fatty liver diseases. Respiratory chain function using a cytoplasmic hybrid (cybrid) assay was further studied in NASH patients and healthy controls. METHODS: Electron microscopy was performed in 26 specimens. Fifteen patients were studied by polymerase chain reaction to detect a 520-bp deletion product of the mitochondrial genome (dmtDNA). Cybrids were created by fusion of platelets with anaerobic neuroblastoma cells in six NASH patients and 12 controls. RESULTS: Eight of ten NASH, one of seven alcoholics and two of nine other patients had linear crystalline inclusions in megamitochondria (p<0.05). Three of five patients with alcohol-related liver disease had dmtDNA compared to one of five NASH patients and one of five non-steatohepatitis controls. Cybrid respiratory chain function in platelets was not different from that of controls. CONCLUSIONS: Respiratory chain dysfunction, if present in NASH, is not expressed in platelet-derived mitochondria. In contrast to alcohol-related liver disease with active drinking, NASH patients do not commonly express the 5-kb mitochondrial DNA gene deletion in liver tissue. As previously described in early alcohol-related liver disease, crystalline inclusions of unknown composition are seen in hepatic mitochondria in NASH. Their presence suggests either an adaptive process or mitochondrial injury.     

Is vitamin D receptor a druggable target for non-alcoholic steatohepatitis?

Nonalcoholic steatohepatitis (NASH) is a progressed stage of non-alcoholic fatty liver disease, and available therapeutic strategies for NASH are limited. Vitamin D receptor (VDR) is proposed as a druggable target for NASH due to the discovery of vitamin D deficiency in NASH patients. To date, vitamin D supplementation has not consistently conferred expected therapeutic benefits,raising the question of whether VDR can serve as a proper drug target for NASH.It is known that VDR can interact with other ligands such as bile acids in addition to vitamin D, and its expression can be induced by fatty acids, and insulin. It has also been shown that while activation of VDR in hepatic macrophages and hepatic stellate cells resulted in attenuation of hepatic inflammation and fibrosis,activation of VDR in hepatocytes could accelerate lipid accumulation. Thus, the multiplicity of VDR ligands, together with the cell type-specificity of VDR activation, must be taken into consideration in assessing the validity of VDR being a potential druggable target for NASH treatment. To this end, we have evaluated the relationship between VDR activation and various contributing factors, such as gut microbiota, bile acid, fatty acids, and insulin, in addition to vitamin D, with an expectation that a potential drug might be identified that can elicit VDR activation in a tissue-and/or cell type-specific manner and therefore achievingtherapeutic benefits in NASH.     

Nonalcoholic steatohepatitis and the metabolic syndrome

Nonalcoholic fatty liver disease (NAFLD) is a major form of chronic liver disease in adults and children. It is one of the consequences of the current obesity epidemic, and can progress to nonalcoholic steatohepatitis (NASH), characterized by steatosis, inflammation, and progressive fibrosis, ultimately leading to cirrhosis and end-stage liver disease. The factors implicated in this progression are poorly understood. NASH is closely associated with obesity and the metabolic syndrome. Recent studies emphasize the role of insulin resistance, oxidative stress, lipid peroxidation, and cytokine release in the development of NASH. This review summarizes the current knowledge on the etiology and pathomechanism of NASH and the role of the metabolic syndrome in NASH development.     

Electron microscopic findings in non‐alcoholic fatty liver disease: Is there a difference between hepatosteatosis and steatohepatitis?

Background and Aims: Non‐alcoholic fatty liver disease has long been accepted as benign; however, recent evidence suggests that the disease may progress to cirrhosis and hepatocellular carcinoma, although the natural course of the disease is still unclear. This study was designed to comparatively evaluate electron microscopic features of non‐alcoholic fatty liver (NAFL) and non‐alcoholic steatohepatitis (NASH). Methods: Quantitative and semi‐quantitative ultrastructural evaluations were performed on liver biopsies from 23 patients, 10 with NAFL and 13 with NASH. Results: No statistically significant difference was noted between NAFL and NASH patients in ultrastructural features of hepatocytes including megamitochondria, intramitochondrial crystalline inclusions, mitochondrial matrix granules, foamy cytoplasmic appearance, electron‐lucent and glycogen‐containing nuclear regions, lipofuscin granules, or an increased frequency of vesicles containing electron‐dense material in peribiliary Golgi zone; however, the mitochondrial diameter was significantly higher in the NASH patients. Intercellular distance and microvilli between hepatocytes, collagen and electron‐dense material accumulation in the space of Disse, electron‐dense material accumulation and microvillus density in bile canaliculi did not differ significantly between the groups. Conclusions: Our data show that, although NAFL and NASH can be distinguished by their distinct light microscopic features, ultrastructural characteristics are similar, which suggests that NAFL may also have the potential to progress to fibrosis and cirrhosis like NASH.     

Rosiglitazone attenuates age- and diet-associated nonalcoholic steatohepatitis in male low-density lipoprotein receptor knockout mice

Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity that can progress to nonalcoholic steatohepatitis (NASH), a serious liver pathology that can advance to cirrhosis. The mechanisms responsible for NAFLD progression to NASH remain unclear. Lack of a suitable animal model that faithfully recapitulates the pathophysiology of human NASH is a major obstacle in delineating mechanisms responsible for progression of NAFLD to NASH and, thus, development of better treatment strategies. We identified and characterized a novel mouse model, middle-aged male low-density lipoprotein receptor (LDLR)(-/-) mice fed a high-fat diet (HFD), which developed NASH associated with four of five metabolic syndrome (MS) components. In these mice, as observed in humans, liver steatosis and oxidative stress promoted NASH development. Aging exacerbated the HFD-induced NASH such that liver steatosis, inflammation, fibrosis, oxidative stress, and liver injury markers were greatly enhanced in middle-aged versus young LDLR(-/-) mice. Although expression of genes mediating fatty acid oxidation and antioxidant responses were up-regulated in young LDLR(-/-) mice fed HFD, they were drastically reduced in MS mice. However, similar to recent human trials, NASH was partially attenuated by an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPARγ) ligand, rosiglitazone. In addition to expected improvements in MS, newly identified mechanisms of PPARγ ligand effects included stimulation of antioxidant gene expression and mitochondrial β-oxidation, and suppression of inflammation and fibrosis. LDLR-deficiency promoted NASH, because middle-aged C57BL/6 mice fed HFD did not develop severe inflammation and fibrosis, despite increased steatosis. Conclusion: MS mice represent an ideal model to investigate NASH in the context of MS, as commonly occurs in human disease, and NASH development can be substantially attenuated by PPARγ activation, which enhances β-oxidation.     

Future Treatments of NASH

NASH is a complex metabolic disease best understood by recognizing the sources and fates of major metabolic substrates (carbohydrates and fatty acids) and how their excess can lead to lipotoxic liver injury with a histological phenotype of NASH. With this perspective, targets of therapy can be predicted. This review summarizes recent clinical trial data and where these trials fit into the substrate overload lipotoxic liver injury paradigm of NASH pathogenesis. Because NASH is likely the result of diverse environmental, genetic, and epigenetic factors that differ among patients, no single therapy is likely to be effective in all patients. Ultimately, rationally designed personalized therapy will be achieved for patients with NASH, but this will require substantial new knowledge on why patients respond to specific therapies, a goal that remains elusive. Hopefully, this gap in knowledge will be addressed by analysis of responders and non-responders in current and future clinical trials.     

The use of statins alone,or in combination with pioglitazone and other drugs,for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement

Non-alcoholic fatty liver disease (NAFLD), the most common liver disease, is characterized by accumulation of fat (> 5% of the liver tissue), in the absence of alcohol abuse or other chronic liver diseases. It is closely related to the epidemic of obesity, metabolic syndrome or type 2 diabetes mellitus (T2DM). NAFLD can cause liver inflammation and progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular cancer (HCC). Nevertheless, cardiovascular disease (CVD) is the most common cause of death in NAFLD/NASH patients. Current guidelines suggest the use of pioglitazone both in patients with T2DM and in those without.The use of statins, though considered safe by the guidelines, have very limited use; only 10% in high CVD risk patients are on statins by tertiary centers in the US. There are data from several animal studies, 5 post hoc analyses of prospective long-term survival studies, and 5 rather small biopsy proven NASH studies, one at baseline and on at the end of the study. All these studies provide data for biochemical and histological improvement of NAFLD/NASH with statins and in the clinical studies large reductions in CVD events in comparison with those also on statins and normal liver. Ezetimibe was also reported to improve NAFLD.Drugs currently in clinical trials seem to have potential for slowing down the evolution of NAFLD and for reducing liver- and CVD-related morbidity and mortality, but it will take time before they are ready to be used in everyday clinical practice. The suggestion of this Expert Panel is that, pending forthcoming randomized clinical trials, physicians should consider using a PPARgamma agonist, such as pioglitazone, or, statin use in those with NAFLD/NASH at high CVD or HCC risk, alone and/or preferably in combination with each other or with ezetimibe, for the primary or secondary prevention of CVD, and the avoidance of cirrhosis, liver transplantation or HCC, bearing in mind that CVD is the main cause of death in NAFLD/NASH patients.     

Current and future treatment options in non-alcoholic steatohepatitis (NASH)

Introduction: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that can progress to cirrhosis and hepatocellular carcinoma. Diagnosis of NASH requires a liver biopsy and is defined as presence of hepatic steatosis, ballooning and lobular inflammation with or without fibrosis. Although NASH is the most common cause of liver disease in the west world and among the top three indications for liver transplantation, there are no universally accepted pharmacological therapies and therapeutic advances have been slow.

Areas covered: Current evidence about lifestyle interventions, bariatric surgery and pharmacotherapy is reviewed. Dietary recommendations and lifestyle interventions have shown promising results but are difficult to maintain. At the moment, there is no universally approved medical treatment for NASH. Pioglitazone and vitamin E are recommended by guidelines in selected patients. An increasing number of phase II and III trials in non-cirrhotic NASH are currently recruiting and their preliminary results discussed.

Expert commentary: As NASH is classified as a medical condition of an unmet therapeutic need, it has gained an accelerated access pathway for drug approval based on surrogate endpoints. It is therefore expected that within the next five years, there will be at least one approved agent for the pharmacological treatment of pre-cirrhotic NASH.     

Hepatocellular carcinoma and non-alcoholic steatohepatitis:The state of play

Hepatocellular carcinoma(HCC) is now the fifth cancer of greatest frequency and the second leading cause of cancer related deaths worldwide. Chief amongst the risks of HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The latter can promote non-alcoholic fatty liver disease(NAFLD), that can lead to the inflammatory form non-alcoholic steatohepatitis(NASH), and can in turn promote HCC. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give a summary of the recent findings that describe and associate NAFLD and NASH with the subsequent HCC progression. We will focus our discussion on clinical and genomic associations that describe new risks for NAFLD and NASH promoted HCC. In addition, we will consider novel murine models that clarify some of the mechanisms that drive NASH HCC formation.     

Nonalcoholic steatohepatitis: definition and pathology

Nonalcoholic steatohepatitis (NASH) is a significant form of chronic liver disease in adults and children. The natural history of NASH ranges from indolent to end-stage liver disease. Current studies are focusing on identification of histologic and/or clinical markers of progression. NASH may be an underlying cause of cryptogenic cirrhosis, and the lesions of NASH may recur in allograft livers. An expanding array of clinical conditions and pathogenetic mechanisms have been identified, but many cases remain "idiopathic"; lack of significant alcohol use is, by definition, common to all cases. Neither clinical evaluation nor laboratory values can ensure either the diagnosis or the exclusion of NASH, and liver biopsy interpretation continues to be considered the "gold standard" for diagnosis. The lesions in NASH are similar but not identical to those of alcoholic steatohepatitis; exact, specific histologic criteria for the diagnosis are currently under discussion. The lesions most commonly accepted for NASH include steatosis, hepatocyte ballooning degeneration, mild diffuse lobular mixed acute and chronic inflammation, and perivenular, perisinusoidal collagen deposition. Zone 3 accentuation may be detected. Mallory's hyaline, vacuolated nuclei in periportal hepatocytes, lobular lipogranulomas, and PAS-diastase-resistant Kupffer cells are common. In biopsy specimens from children, portal inflammation may be more prominent than in adults. Progression of fibrosis may result in bridging septa and cirrhosis. The lesions of steatohepatitis may be noted concurrently with other forms of chronic liver disease. A histological "grading and staging" system has been developed to reflect the unique features of steatohepatitis, gradations of severity and fibrosis, and to promote uniform reporting of the histopathology.     

Motion - all patients with NASH need to have a liver biopsy: arguments against the motion.

Most cases of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are suspected on the basis of the exclusion of viral, autoimmune, metabolic and genetic causes of chronic liver disease in patients with chronic elevation of aminotransferase enzymes. However, the definitive diagnosis of NASH requires liver biopsy. Valuable blood tests include hepatitis B and C serology, iron profile, alpha 1-antitrypsin phenotype, ceruloplasmin, antinuclear antibody and antismooth muscle antibody, and serum protein electrophoresis. If these tests are negative or normal, and if there are no symptoms or signs of chronic liver disease, it is unlikely that a specifically treatable liver disease would be discovered at biopsy. The prevalence of NAFLD in the general population appears to be approximately 20%, and 2% to 3% of people have NASH. There is no proven specific therapy for the spectrum of nonalcoholic liver disease; therefore, the management of the patient with NASH is not likely to be changed after histological assessment. Bleeding, sometimes fatal, and other complications requiring hospitalization can occur, and liver biopsies should not be undertaken without clear clinical indications. The high cost of undertaking histological assessment of all persons with asymptomatic elevations of liver enzymes cannot be justified in view of the risks and limited clinical benefits.