Natural History Of Nonalcoholic Steatohepatitis Research Articles

Natural history of NASH cirrhosis in liver transplant waitlist registrants

Non-alcoholic steatohepatitis (NASH) cirrhosis is rapidly growing as an indication for liver transplant(ation) (LT). However, the natural history of NASH cirrhosis among LT waitlist registrants has not been established. The present study aimed to define the natural history of NASH cirrhosis using the Scientific Registry of Transplant Recipients database. The study cohort comprised patients registered on the LT waitlist between 1/1/2016 to 12/31/2021. The primary outcomes included probability of LT and waitlist mortality, comparing NASH (n= 8,120) vs. non-NASH (n= 21,409) cirrhosis. Patients with NASH cirrhosis were listed with lower model for end-stage liver disease (MELD) scores despite bearing a greater burden of portal hypertension, especially at lower MELD scores. The overall transplant probability in LT waitlist registrants with NASH [vs. non-NASH] cirrhosis was significantly lower at 90 days (HR 0.873, p <0.001) and 1 year (HR 0.867, p <0.001); this was even more pronounced in patients with MELD scores >30 (HR 0.705at 90 days and HR 0.672at 1 year, p <0.001 for both). Serum creatinine was the key contributor to MELD score increases leading to LT among LT waitlist registrants with NASH cirrhosis, while bilirubin was in patients with non-NASH cirrhosis. Finally, waitlist mortality at 90 days (HR 1.15, p <0.001) and 1 year (1.25, p <0.001) was significantly higher in patients with NASH cirrhosis compared to those with non-NASH cirrhosis. These differences were more pronounced in patients with lower MELD scores at the time of LT waitlist registration. LT waitlist registrants with NASH cirrhosis are less likely to receive a transplant compared to patients with non-NASH cirrhosis. Serum creatinine was the major contributor to MELD score increases leading to LT in patients with NASH cirrhosis. This study provides important insights into the distinct natural history of non-alcoholic steatohepatitis (NASH) cirrhosis among liver transplant (LT) waitlist registrants, revealing that patients with NASH cirrhosis face lower odds of transplantation and higher waitlist mortality than those with non-NASH cirrhosis. Our study underscores the significance of serum creatinine as a crucial contributor to model for end-stage liver disease (MELD) score in patients with NASH cirrhosis. These findings have substantial implications, emphasizing the need for ongoing evaluation and refinement of the MELD score to more accurately capture mortality risk in patients with NASH cirrhosis on the LT waitlist. Moreover, the study highlights the importance of further research investigating the impact of the implementation of MELD 3.0 across the US on the natural history of NASH cirrhosis.

A diabetologist's perspective of non-alcoholic steatohepatitis (NASH): Knowledge gaps and future directions.

There is a close link between steatohepatitis (NASH) and Type 2 diabetes (T2DM). Recently, the American Diabetes Association (ADA) recommended screening for NASH and advanced fibrosis in patients with diabetes and hepatic steatosis or elevated plasma alanine aminotransferase (ALT). This is because as many as ~30% to 40% may have NASH and ~10% to 15% advanced fibrosis. The role of hyperglycemia and the natural history of NASH in diabetes remain poorly understood, as well as which diagnostic algorithm or interventions are most cost-effective. There is significant clinical inertia and most patients today are still not receiving adequate lifestyle intervention or pharmacological treatment with diabetes agents known to be effective against NASH. Lifestyle intervention improves steatohepatitis in proportion to the magnitude of weight loss, but this trend is not as consistent for regression of fibrosis. This limited success supports the need for concomitant pharmacological therapy. Pioglitazone has been shown to consistently induce resolution of NASH in both patients with or without diabetes in a total of 498 participants in five randomized controlled trials (RCTs), but with modest effects on liver fibrosis. Proof-of-concept studies suggest a potential role for GLP-1RAs and SGLT2 inhibitors. Combination therapy is on the horizon. Treating diabetes and NASH with a combination of pioglitazone, GLP-1RAs or SGLT2i, could be a cost-effective strategy to treat both diseases while reducing their high cardiovascular risk. Future combination therapies will likely combine existing diabetes agents with novel NASH-spechfic drugs under development. This review highlights current knowledge gaps and proposes future directions for the treatment of NASH in diabetes.

Disease progression of nonalcoholic steatohepatitis in Taiwanese patients: a longitudinal study of paired liver biopsies

Nonalcoholic steatohepatitis (NASH) might progress to fibrosis, cirrhosis, and hepatocellular carcinoma. However, the natural history of NASH has not been fully clarified. This study aimed to investigate the disease progression in NASH patients receiving paired liver biopsies. We also aimed to examine the factors associated with NASH progression. Ten NASH patients who had received liver biopsies during June 2001 and February 2010 were consecutively enrolled. The histopathological changes were examined retrospectively, including nonalcoholic fatty liver disease activity score (NAS) and fibrosis stage. The associated clinical profiles were also analyzed. The median duration between paired biopsies was 20.5 months (range: 12-106 months). According to NAS and fibrosis stage, disease progression, stable disease, and disease regression were observed in seven patients, two patients, and one patient, respectively. Six (60%) patients had increased NAS on second biopsy, and two were lean NASH patients. The only patient with an improvement in NAS had achieved body weight reduction (13.3%) between paired biopsies. None of the 10 patients experienced an improvement in fibrosis. Five (50%) patients showed progression of fibrosis on second biopsy and the annual fibrosis progression rate was 0.32/year. Two of the five patients who showed progression of fibrosis were of the nonobese phenotype, whereas three patients were nondiabetic. NASH is a progressive disease in Taiwanese patients. The disease progression should be further clarified in lean and nondiabetic NASH patients.

Fat and liver transplantation: clinical implications.

Nonalcoholic steatohepatitis (NASH), with or without hepatocellular carcinoma, is a growing indication for liver transplantation (LT) worldwide, particularly in the Western world. Patients with NASH typically combine features of metabolic syndrome with cardiovascular comorbidities, which challenge pre-LT evaluation, surgical approaches, post-LT management, and outcomes. Post-LT survival in NASH patients is excellent, similar to that achieved with other indications, particularly in the absence of cardiovascular comorbidities. Although disease recurrence on the liver allograft is common, progression to advanced disease is uncommon, at least in the short term. Whether this holds true with longer follow-up remains to be determined. Owing to the increased prevalence of nonalcoholic fatty liver disease worldwide, along with a shortened organ pool donation in many countries, utilization of donor grafts with hepatic steatosis is now more common. Understanding the limitations of these grafts as well as potential mechanisms to improve graft quality and/or transplant outcome is clue for transplant centers. In this review, we will summarize current data on evaluation of NASH patients and whether it differs from that applied to other candidates, the natural history of NASH both pre- and post-transplantation, emphasizing on waiting list management and recurrence of the original disease in the new graft as well as post-transplant outcome. Finally, we will discuss the current use of steatotic liver donors and strategies to improve outcome when using this type of grafts.

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Su1958 A Novel Murine Model Recapitulates the Pathogenesis of Human Non-Alcoholic Steatohepatitis (NASH) and NASH-Related Hepatocellular Carcinoma

Non-alcoholic steatohepatitis (NASH) is a pathological liver condition that occurs in the absence of alcohol abuse and is characterized histologically by steatosis, lobular inflammation, hepatocyte ballooning and fibrosis. NASH is a progressive disease that can lead to hepatocellular carcinoma (HCC), and there is a growing need in the therapeutic field for a reliable and clinically relevant model system that recapitulates the natural history of NASH and encompasses hallmark changes in gene expression, cellular dynamics and metabolic parameters. We have developed a novel NASH mice model (STAMTM) by neonatal low-dose streptozotocin injection to induce a diabetic state in mice and high-fat diet feeding to develop steatosis and mild chronic hepatic inflammation from 4 weeks of age onwards. The STAMTM model reproduced the pathological course of NASH, with step-wise disease progression from simple steatosis to HCC in a relatively short time (NASH and HCC were evident at 8 and 18 weeks after birth, respectively). It showed typical features of human NASH especially as indicated by the following. 1) Histopathology: microand macro-vesicular fat deposition, inflammatory cell infiltration, hepatocyte ballooning and fibrosis, with NAFLD Activity score of 5 at 8 weeks of age. 2) Hepatic gene expression profiles: up-regulation of TNF-α, TGFβ, MCP-1, TIMP-1, α-SMA and collagen Type 1 and 3. In the STAMTM mice, steatohepatitis with lobular fibrosis was evident at 8 weeks of age, which was much earlier than conventional animal models. Furthermore, almost all STAMTM mice developed HCC, with macroscopic appearance of tumor nodules observed at 18 weeks of age on average. These characteristics, together with reproducibility of the disease onset and regularity of the progression, endow the STAMTM model with advantages as a useful preclinical NASH model. Body weight, fasting blood sugar, serum AST, serum ALT, Liver TG, NAS

Association of Tumor Necrosis Factor α and Manganese Superoxide Dismutase Polymorphisms in Patients with Non-Alcoholic Steatohepatitis from Northeast Mexico

Background and Aims: Environmental and genetic factors play a role in the pathogenesis and natural history of non-alcoholic steatohepatitis (NASH). The aim of this study was to determine if the G-238A (allele TNFA) and G-308A (allele TNF2) tumor necrosis factor-alpha (TNF- ) and Ala9Val manganese superoxide dismutase (MnSOD) polymorphisms were associated with NASH in a case-control study of subjects from Northeast Mexico. Methods: We analyzed DNA samples from 68 patients with NASH (50 women and 18 men; mean age ± SD, 33.9 ± 10.8 years; BMI 43.9 ± 7.2 kg/m 2 ) and 100 healthy subjects (44 women and 56 men; mean age ± SD, 27.8 ± 10.8 years; BMI 23 ± 1.6 kg/m 2 ). The diagnosis was based on liver biopsy reviewed by two pathologists blinded to clinical data. The polymorphisms were evaluated using the polymerase chain reaction-restriction fragment length polymorphism method. Results: The frequency of G-238A TNF- and Ala9Val MnSOD polymorphisms in NASH patients was significantly higher in comparison with control subjects (OR = 3.06, 95% CI 1.29-7.33, p = 0.0047 and OR = 6.28, 95% CI 2.95-13.55, p = 0.001, respectively). In contrast, the G-308A TNF- polymorphism did not show a statistical difference between either group (OR = 1.04, 95% CI 0.45-2.38, p = NS). Analyzed populations were in Hardy-Weinberg equilibrium. Conclusions: Our results suggest that G-238A TNF- and Ala9Val MnSOD polymorphisms, which are molecules involved in inflammation and cellular oxidative stress, could be associated with NASH. These data may contribute to understanding the genetic susceptibility to NASH.

Which Clinical and Sonographic Parameters May Be Useful to Discriminate NASH from Steatosis?

The natural history of nonalcoholic steatohepatitis (NASH) includes the passage through steatosis. To retrospectively evaluate the usefulness of sonographic parameters compared to histological diagnosis when differentiating steatosis from NASH. This retrospective study reviewed records of patients with steatosis from databases of our Departments, selecting only those who had been diagnosed by sonography and liver biopsy [64 males (63.82%); 30 females (36.18%)]. Attenuation of the echo amplitude (P<0.05; odds ratio (OR): 3.43; confidence interval (CI): 1.02-11.57), focal fat sparing (P<0.05; OR: 3; CI: 1.02-11.88) and splenic diameter (P<0.05; OR: 1.66; CI: 1.04-3.26) were independent predictors of NASH. A significantly higher association of attenuation of the echo amplitude, enlarged splenic diameter, and presence of focal fat sparing was observed in NASH patients (P<0.01). It is very difficult to build a predictive system to distinguish NASH from steatosis based on sonographic scores. However, it is already possible to differentiate NASH from steatosis by combining 3 simple sonographic parameters: attenuation of the echo amplitude, enlarged splenic diameter, and presence of focal fat sparing.

Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis

There have been few reports on hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) and the natural history of NASH. Accordingly, we assessed the clinical features of HCC in NASH, the risk factors for HCC, and natural history of NASH with advanced fibrosis. There were 34 NASH patients with HCC and 348 NASH patients without HCC. To clarify the clinical features of NASH patients with HCC and to determine the risk factors for HCC, we compared NASH patients with HCC with those without HCC. Univariate and multivariate logistic regression models were used for statistical analysis. A prospective cohort study of the outcomes of 137 NASH with advanced fibrosis was started in 1990. The impact of baseline risk factors on the development of HCC and survival was evaluated by Cox regression analysis. In total, 88% of patients with HCC had advanced fibrosis, with a median age of 70 years. Older age, low level of AST, low grade of histological activity, and advanced stage of fibrosis were risk factors for HCC. A prospective cohort study showed that the 5-year cumulative incidence of HCC was 7.6%, and the 5-year survival rate was 82.8%. HCC was the leading cause of death. The present study confirmed that older age and advanced fibrosis were important risk factors for HCC, and that HCC was the major cause of mortality in NASH patients with advanced fibrosis. Regular screening for HCC is thus extremely important for NASH patients with advanced fibrosis.

Recent advances in nonalcholic fatty liver disease

The purpose of this review is to summarize recent advances in defining the clinical features, pathophysiology, natural history, and treatment of nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease is present in approximately 30% of the US population. A histologic grading and staging system has been developed and validated. Nonalcoholic fatty liver disease increases the risk of developing the metabolic syndrome. The presence and severity of nonalcoholic fatty liver disease correlates with the severity of obesity, fat distribution, age, and presence of other features of the metabolic syndrome. Fifteen to 20% of subjects with nonalcoholic steatohepatitis develop cirrhosis. Hepatic steatosis is associated with an increase in both free fatty acid delivery to the liver for re-esterification and increased de-novo lipogenesis. Several mechanisms of hepatocyte injury and death including free fatty acid toxicity, increased free cholesterol, cytokine-mediated injury and activation of the unfolded protein response have been defined. While many therapeutic targets have been identified and pilot studies performed, a definitive treatment for nonalcoholic steatohepatitis remains to be established. Nonalcoholic fatty liver disease is a widely prevalent disease that is critically linked to insulin resistance and the metabolic syndrome. While much new information on the pathogenesis and natural history of nonalcoholic steatohepatitis is available, an effective therapy remains to be established.

Current and novel therapies for the treatment of nonalcoholic steatohepatitis

The worldwide epidemic of obesity and the metabolic syndrome has made nonalcoholic fatty liver disease (NAFLD), one of the most important liver diseases of our time. NAFLD is now the commonest cause of abnormal liver test results in industrialized countries and its incidence is rising. The current treatment of nonalcoholic steatohepatitis (NASH) has focused on lifestyle modification to achieve weight loss and modification of risk factors, such as insulin resistance, dyslipidemia, and hyperglycemia associated with the metabolic syndrome. With our increasing understanding of the pathogenesis of NASH, have come a plethora of new pharmacologic options with great potential to modify the natural history of NAFLD and NASH. This article focuses on a number of novel molecular targets for the treatment of NASH as well as the evidence for currently available therapy. It should be noted, however, that in part because of the long natural history of NASH and NAFLD, no therapy to date has been shown to unequivocally alter liver-related morbidity and mortality in these patients.

Late complications of NASH: a challenge for hepatologists

Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, Hall P, Khan M, George J. Data on the long-term outcome of nonalcoholic steatohepatitis (NASH)-associated cirrhosis are few, and most reports describe cases of cryptogenic cirrhosis associated with risk factors for NASH but without histologic definition. In this prospective cohort study, we describe the long-term morbidity and mortality of 23 patients with NASH-associated cirrhosis defined by strict clinicopathologic criteria. Outcomes were compared with 46 age- and gender-matched patients with cirrhosis from chronic hepatitis C virus (HCV) infection: 23 untreated and 23 nonresponders to antiviral therapy. During follow-up (mean, 84 months; median, 60 months; range, 5–177 months), 9 of the 23 NASH-associated cirrhosis cases developed liver-related morbidity (8 ascites and/or encephalopathy, 1 variceal bleeding). The probability of complication-free survival was 83, 77, and 48% at 1, 3, and 10 years, respectively, and the cumulative probability of overall survival was 95, 90, and 84% at 1, 3, and 10 years, respectively. Five deaths were from liver failure, 1 from a non-liver-related cause. By multivariate analysis, bilirubin ( P =0.02) and platelet ( P =0.04) were independent predictors of complication-free survival; bilirubin ( P =0.05) was the only predictor for overall survival. After controlling for these factors, there was no difference in complication-free or overall survival between the NASH-cirrhosis cohort and either group of HCV-cirrhosis. However, 8 cases of liver cancer occurred in the HCV-cirrhosis groups compared with none among NASH cases. In conclusion, liver failure is the main cause of morbidity and mortality in NASH-associated cirrhosis. The prognosis is either similar or less severe than HCV-cirrhosis, except that HCC appears less common. [Abstract reproduced by permission of Hepatology 2003;38:420–427].

Contribution of metabolic factors to alanine aminotransferase activity in persons with other causes of liver disease

Nonalcoholic fatty liver disease has been defined by the presence of hepatic steatosis in the absence of other chronic liver diseases. We sought to determine whether obesity, insulin resistance, and the metabolic syndrome, which are the main risk factors for nonalcoholic fatty liver disease, are associated with similar elevations in serum alanine aminotransferase activity in persons with and those without other causes of chronic liver disease. Adult participants of the third National Health and Nutrition Examination Survey were divided into those with causes of chronic liver disease (n = 1037), defined as viral hepatitis, excessive alcohol consumption, or increased transferrin-iron saturation, and those without (n = 8004). Among persons with other causes of chronic liver disease, obesity (adjusted odds ratio, 4.9; 95% confidence interval, 2.5-9.4), insulin resistance (adjusted odds ratio, 6.8; 95% confidence interval, 3.0-15.5, comparing the highest and the lowest quartile), and the metabolic syndrome (adjusted odds ratio, 3.3; 95% confidence interval, 1.4-8.0) were all strongly associated with increased alanine aminotransferase activity (>43 IU/L). Among persons without other causes of chronic liver disease, statistically similar associations were identified. Obesity, insulin resistance, and the metabolic syndrome are strong predictors of increased alanine aminotransferase activity in the US population, both in persons with and in persons without other causes of chronic livers disease. We hypothesize that metabolic fatty liver disease related to these conditions is the cause of the increased alanine aminotransferase activity and may be underrecognized in persons with other causes of chronic liver disease.

Nonalcoholic steatohepatitis: cirrhosis, hepatocellular carcinoma, and burnt-out NASH

Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by the histological features of steatohepatitis in the absence of significant alcohol consumption. The natural history of NASH is poorly defined. Here we report our experience with a patient to illustrate the clinical course of cirrhotic NASH. A 67-year-old woman was admitted with hematemesis due to the rupture of esophageal varices. Her varices were treated by endoscopic ligation and endoscopic sclerotherapy. Her medical history was unremarkable. Both the patient and her family members were asked about alcohol intake several times during her illness, but all of them denied a history of alcohol intake. She had insulin resistance, as determined by homeostasis model assessment. Serological tests for viral hepatitis were all negative. Viral hepatitis, autoimmune liver disease, iron overload, and metabolic liver disorders were all excluded. Imaging tests failed to reveal any steatosis, because of the presence of severe fibrosis. Liver biopsy showed moderate steatosis, moderate inflammation, ballooning degeneration, and Mallory bodies. We diagnosed NASH associated with cirrhosis based on the clinicopathological features. Almost 2 years later, she developed hepatocellular carcinoma (HCC) and she died of multiple HCCs. At autopsy, tumor invasion was seen throughout liver segment 8. The noncancerous liver showed burnt-out NASH; the steatosis, necroinflammation, ballooning degeneration, and Mallory bodies had all disappeared. In Japan, the prevalence of nonalcoholic fatty liver disease will increase as obesity has been increasing, so it is important to understand how to diagnose NASH. When a patient has NASH, careful follow-up should be performed.

The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver diseasePowell EE, Cooksley WGE, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years [Hepatology 1990; 11:74–80

The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver diseasePowell EE, Cooksley WGE, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years [Hepatology 1990; 11:74–80

The importance of routine liver biopsy in diagnosing nonalcoholic steatohepatitis in bariatric patients.

Nonalcoholic Steatohepatitis (NASH) commonly occurs in obese patients and predisposes to cirrhosis. Prevalence of NASH in bariatric patients is unknown. Our aim was to determine the role of routine liver biopsy in managing bariatric patients. Prospective data on patients undergoing Roux-en-Y gastric bypass (RYGBP) was analyzed. One pathologist graded all liver biopsies as mild, moderate or severe steatohepatitis. NASH was defined as steatohepatitis without alcoholic or viral hepatitis. Consecutive liver biopsies were compared to those liver biopsies selected because of grossly fatty livers. 242 patients underwent open and laparoscopic RYGBP from 1998-2001. Routine liver biopsies (68 consecutive patients) and selective liver biopsies (additional 86/174, 49%) were obtained. Findings of cirrhosis on frozen section changed the operation from a distal to a proximal RYGBP. The two groups were similar in age, gender, and BMI. The group with the routine liver biopsies showed a statistically significant larger preponderance of NASH (37% vs 32%). Both groups had a similar prevalence of cirrhosis. Neither BMI nor liver enzymes predicted the presence or severity of NASH. Routine liver biopsy documented significant liver abnormalities in a larger group of patients compared with selective liver biopsies, thereby suggesting that liver appearance is not predictive of NASH. Liver biopsy remains the gold-standard for diagnosing NASH. We recommend routine liver biopsy during bariatric operations to determine the prevalence and natural history of NASH, which will have important implications in directing future therapeutics for obese patients with NASH and for patients undergoing bariatric procedures.

Treatment of non-alcoholic steatohepatitis

Treatment of patients with non-alcoholic steatohepatitis (NASH) has typically been focused on the management of associated conditions such as obesity, diabetes mellitus and hyperlipidaemia. NASH associated with obesity may resolve with weight reduction, although the benefits of weight loss have been inconsistent. Appropriate control of glucose and lipid levels is always recommended, but is not always effective in reversing the liver condition. Results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, α-tocopherol, metformin and thiazolidinedione derivatives suggest that these medications may be of potential benefit for patients with NASH. These medications, however, need first to be tested in well-controlled trials with clinically relevant end-points and extended follow-up. A better understanding of the pathogenesis and natural history of NASH will help to identify the subset of patients at risk of progressing to advanced liver disease and, hence, those patients who should derive the most benefit from medical therapy.

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.GASTROENTEROLOGY 2001;121:710-723

Nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is an hepatic disorder with histologic features of alcohol-induced liver disease that occurs in individuals who do not consume significant alcohol. NASH is believed to be one of the most common explanations for abnormal liver chemistries in American adults. Risk factors for NASH include obesity, type II diabetes, hyperlipidemia, total parenteral nutrition, jejuno-ileal bypass surgery, and the use of certain drugs. However, some patients with NASH have no identifiable risk factors for the disease. Clinically, NASH is a diagnosis of exclusion that should be suspected as a cause of chronic hepatitis in patients who deny significant alcohol consumption and have negative serologic tests for congenital and other acquired causes of liver disease. The identification of fatty liver on imaging studies supports the diagnosis of NASH, which can be established definitively by liver biopsy. The latter also provides useful prognostic information since most patients with simple steatosis follow an indolent clinical course, whereas those with steatohepatitis, fibrosis, or cirrhosis are more likely to develop clinically significant complications of liver disease. Weight reduction and treatment of confounding medical conditions are the mainstays of therapy for NASH. However, there is little evidence that any of the current treatments prevent progression to more histologically advanced stages of NASH. Several experimental therapies, including treatment with bile acids, antibiotics, nutritional supplements, and antioxidants, have had anecdotal success in selected patients, but improved understanding of the pathogenesis and natural history of NASH will be required to develop generally effective therapy for the disorder.

The natural history of nonalcoholic steatohepatitis: A follow-up study of forty-two patients for up to 21 years

Forty-two patients with nonalcoholic steatohepatitis were followed for a median of 4.5 yr (range = 1.5 to 21.5 yr). Except for two patients with lipodystrophy, all were obese; 35 of 42 were women, 26 of 32 were hyperlipidemic and 15 were hyperglycemic. Upper abdominal pain was the most common reason for presentation. Initial liver biopsy specimens showed the presence of macrovesicular fatty infiltration, lobular (acinar) inflammation, apoptosis, Mallory bodies (in four cases) and fibrosis (in 18 cases). Cirrhosis was present at initial diagnosis in one subject and in another two subjects liver biopsy showed marked fibrosis with disturbed architecture. Serial liver biopsy specimens revealed minimal or no apparent progression of the disorder in most of the patients, in keeping with their benign clinical course. However, one patient showed progression from fibrosis to cirrhosis during the 5-yr observation period, and in the patients with extensive fibrosis the liver disease evolved from one of active inflammation to one of inactive cirrhosis without fat or inflammation. The patient with cirrhosis later died of hepatocellular carcinoma. The severity or type of hepatic change did not correlate with the degree of obesity, hyperlipidemia or hyperglycemia. However, in individual patients, poorly controlled diabetes and rapid weight loss preceded the onset of steatohepatitis. We conclude that nonalcoholic steatohepatitis is a cause of hepatic inflammation histologically resembling that of alcohol-induced liver disease but usually slowly progressive and of low-grade severity. However, the disorder may ultimately result in cirrhosis. Nonalcoholic steatohepatitis should be distinguished from alcoholic steatohepatitis and recognized as a further cause of "cryptogenic cirrhosis."