Clinical and histological features of nonalcoholic steatohepatitis in Iranian patients
© Bahrami et al; licensee BioMed Central Ltd. 2003
Received: 14 March 2003
Accepted: 16 October 2003
Published: 16 October 2003
Although several studies have been performed on risk factors and natural course of NASH, it seems that NASH tends to be more than a disease confined to strict boundaries. The objective of this study was to assess the clinical and paraclinical features and risk factors for non-alcoholic steatohepatitis (NASH) patients in an Iranian population
Patients with histologically confirmed NASH who had elevated liver aminotransaminases, negative serologic markers of viral or autoimmune hepatitis and no findings in favor of metabolic liver disease were enrolled. A careful history was taken regarding alcohol intake.
53 patients consisting of 32 male and 21 female entered the study. The mean age was 37.8 ± 11.3 years. Twenty-six patients (55.3%) were overweight, 15 (31.9%) obese, 40 (75.5%) dyslipidemic, and three patients (5.7%) were diabetic. Liver biopsy showed mild steatosis in 35.7%, moderate steatosis in 53.6%, and severe forms in 10.7%. In 80.2% of patients, portal inflammation was present, and 9.4% had cirrhosis. The amount of increase in liver enzymes bore no relationship with fibrosis, portal inflammation, and degree of steatosis.
The patients in our study showed a male predominancy and were somewhat younger than other studies.
KeywordsNonalcoholic steatohepatitis liver biopsy Nonalcoholic Fatty liver disease steatosis obesity Epidemiology
Non-alcoholic steatohepatitis (NASH) is a disease of unknown origin characterized histologically by changes similar to what is seen in alcoholic-like liver injury but in the absence of significant alcohol intake [1, 2]. NASH is considered a type of chronic hepatitis and is a severe form of a spectrum called non-alcoholic fatty liver disease (NAFLD) . NAFLD has four histological stages: (1) fatty infiltration of the liver (2) fatty infiltration plus inflammation (3) fatty infiltration with ballooning degeneration (4) fatty infiltration with lesions similar to alcoholic hepatitis and sinusoidal fibrosis, polymorphonuclear infiltration with or without Mallory hyaline. NASH is the name given to the third and fourth stages [4, 5].
The prevalence and clinical significance of NASH appears to be more than what is generally believed [6–11]. Among patients who have had liver biopsies, NASH is seen in approximately 7 to 9 percent in Western countries [12, 13]. Ultrasonographic studies on normal population show a prevalence of 25 percent for NAFLD in the United States [5, 14]. The disease predominantly occurs between the ages of 40 and 60, [9, 11, 15] although there have been reports in children over the age of 10 [16, 17] NASH is frequently associated with disorders such as insulin resistance, obesity, type 2 diabetes mellitus, hyperlipidemia, protein-calorie malnutrition, and jejeunoileal bypass surgery [5, 9, 12, 18–21] It is important to consider that NASH can progress to cirrhosis and hepatic failure [7, 8], further underscoring its importance as a potentially serious and life-threatening disease.
Regarding this fact that in Iran alcohol consumption is much less than western countries, we doubted whether the demography and risk factors of NASH in Iranian populations is the same as what has been seen in previous studies.
The cohort of patients reviewed here were selected from all patients between 15 and 65, referred to Gastroenterology and Hepatology Clinic of Imam Khomeini Hospital, Tehran, Iran, from March 20, 1999 to November 21, 2001. Inclusion criteria were: 1. elevated liver aminotransaminases 2. histologic confirmation of nonalcoholic steatohepatitis 3. negative serologic markers of viral or autoimmune hepatitis (including HBsAg, HCV antibody (ELISA), HIV antibody (ELISA), antinuclear antibodies, anti-smooth muscle antibodies, and anti-liver/kidney microsomes type 1 antibodies) 4. no findings in favor of metabolic liver diseases, including Wilson's disease and hemochromatosis) and negative alpha-1 antitrypsin. A careful history was taken with special attention to alcohol intake and ultrasonography was performed in all enrolled patients. Alcohol intake was asked from the patient and at least one of the patients' companions. In case of positive alcohol consumption, the questionnaire used for this purpose had more detail to help the interviewer to estimate the approximate amount of alcohol consumption. Exclusion criteria were: 1. recent gastrointestinal surgery 2. pregnancy 3. usage of drugs known to result in steatosis, including glucocoticoids, synthetic esterogens, aspirin, tamoxifen, amiodarone, Calcium-channel blockers, and methotrexate.
Of 213 patients (108 male and 105 female) who have primarily been studied for elevation of serum aminotransferases in the beginning, 72 patients who had inclusion criteria, except pathologic confirmation, consented to undergo liver biopsy. The pathologic diagnosis of NASH was confirmed in 53 patients and these patients were analyzed. Also we used the demographic data of the other 21 patients to avoid any selection bias in this characteristics, which sounded to be different in our study, comparing with previous studies.
Laboratory and pathological studies
Abdominal obesity, defined as a waist circumference in men >102 cm (40 in) and in women >88 cm (35 in)
Triglycerides ≥150 mg/dL
HDL cholesterol <40 mg/dL in men and <50 mg/dL in women
Blood pressure ≥ 130/ ≥85 mmHg
Fasting glucose ≥110 mg/dL
Risk factors for NASH, according to previous studies, included diabetes mellitus, hyperlipidemia, obesity, history of significant weight loss or weight gain, history of consumption of esterogens or androgens, and extensive abdominal surgery.
The results of quantitative variables are presented as mean ± SD and those of qualitative variables as numbers and percentages. T test was used to compare quantitative variables between subgroups of patients, and differences between categorical variables were analyzed by Chi Square. Logistic regression analysis was used to assess the effect of different factors on histological findings in liver biopsy specimens. A significance level of 0.05 was used.
Anthropometric and biochemical characteristics of 53 patients with NASH
36.0 ± 10.6
40.5 ± 11.9
37.8 ± 11.3
93.6 ± 16.5*
69.3 ± 12.0
83.8 ± 19
30.7 ± 4.9†
27.3 ± 3.5
29.3 ± 4.7
Normal BMI, n (%)
Obesity, n (%)
Overweight, n (%)
Total cholesterol (mg/dL)
229.6 ± 73.5
223.5 ± 62.5
227.0 ± 68.5
139.5 ± 42.3
123.0 ± 43.3
134.8 ± 42.2
47.6 ± 16.1
43.1 ± 13.6
46.3 ± 15.2
207 ± 83.6
184 ± 89.1
197.3 ± 85.8
102.1 ± 11.4
112.8 ± 42.5
106.5 ± 28.1
80.3 ± 27.5
82.0 ± 38.8
80.9 ± 32.0
68.8 ± 22.4
71.3 ± 37.5
69.8 ± 28.9
0.9 ± 0.3
0.9 ± 0.5
0.9 ± 0.4
Three patients (5.7%) had overt diabetes mellitus. Forty patients (75.5%) had some form of dyslipidemia; in 66.0% serum cholesterol was high, in 60.4% hypertriglyceridemia was present, and both cholesterol and triglycerides were high in 50.9%. Insulin resistance was observed in 29 patients (54.7%). Seven patients (13.2%) had none of the risk factors usually associated with NASH. The mean ALT and AST levels were 80.9 ± 32.0 IU/L and 69.8 ± 28.9 IU/L, respectively. Mean AST to ALT ratio was 0.9 ± 0.4. This ratio was below 1 in 65.3% of patients and below 2 in 96.2%.
In 31 patients (58.5%) abnormal ultrasound findings were observed; 17% of all patients had increased liver size, and 50.9% had hyperechogenicity, indicating fatty liver.
Liver biopsy showed that steatosis was mild in 35.7%, moderate in 53.6%, and severe in 10.7%. 22 patients (41.5%) had mild, 26 patients (49.1%) moderate and 5 patients (9.4%) had severe necroinflammatory grades. In histological staging of fibrosis, 11.3%, 18.9%, 22.6%, and 37.7% of patients had 0 through 3 scores, respectively and in 9.4% (5 patients), liver biopsy demonstrated cirrhosis (stage 4). The results of logistic regression analysis showed no relationship between the level of liver enzymes and fibrosis, necroinflammatory grading, and steatosis. Presence of insulin resistance did not have any significant relationship with the staging and grading of the disease, as well.
In an analysis of demographic characteristics of 53 histologically-confirmed NASH cases and 21 patients with clinical diagnosis of NASH whose diagnosis was not confirmed in biopsy, 56.8% of patients (42/74) were male and 43.2% (32/74) were female. Mean age was 39.2 ± 12.1 years and mean BMI was 29.1 ± 4.1 kg/m2. There was no significant difference in these characteristics between those who had positive biopsy and those who had negative.
Nonalcoholic fatty liver disease (NAFLD) seems to have become an important medical entity and this importance is mainly resulted from its potential to progress to cirrhosis and liver failure and its common occurrence in general population . Because of the low rate of alcohol consumption in Iran, the prevalence might be even higher than other countries. Regardless of the religious beliefs, the habit of alcohol consumption in Iranian population, in most instances, is not so heavy and frequent as what is seen in most of the western countries.
Our patients were somewhat younger than those in previous studies (40–60 years old) [9, 12, 15]. Also most of our patients were male (60.4%), while most of the previous series showed a female predominance [10–12, 19] and only a few had more male patients than females . One of the reasons for these differences might be the failure to rigorously rule out hepatitis C in some of the studies. We rechecked all patients with mild steatosis for hepatitis C infection. In the report mentioned before as showing a male preponderance , also hepatitis C was excluded with precision, and the patients had demographic characteristics different from those usually reported. The male predominancy in our study, prompted us to evaluate whether this difference is related to the disease, itself, or is a selection bias in patients who are referred to our clinic. We compared these patients with other patients who primarily had elevation of serum aminotransferases but did not meet the inclusion criteria of the study. From total number of 127 patients with aminotransferases elevation who were excluded from the study, 52.8% were male. Although not exclusively rejecting the selection bias, these findings are against the assumption of a selection bias, since there is not a significant male predominance in other patients of our clinic. But more investigations are mandatory in this regard. Another probable justification of the different sex composition of our patients might be attributed to the lower rate of alcohol consumption in our society. Since men usually consume more amount of alcohol and are more at risk of alcoholic liver disease, in societies with higher prevalence of alcohol consumption, more men are excluded from the diagnosis of nonalcoholic steatohepatitis because of their alcohol consumption.
The mean weight of the patients was higher than normal as in previous reports. [11, 12, 18] Most patients had abnormally high BMI's and 94.2% had weights more than 10% above their ideal body weights. 11.3% of the patients had a history of weight loss in the year before diagnosis, which is similar to other results [24, 25].
Another difference between our results and other reports is the relatively low prevalence of diabetes. Although some reports have shown a prevalence of 2–5% for diabetes mellitus in this group [19, 26], in most of them this prevalence is as high as 21–55% [12, 9–11, 18–21]. An interesting finding is that 13.2% of our patients had none of the known risk factors for development of NASH, and NASH should be considered as an entity not being confined to obese and diabetic patients.
Liver enzyme levels in our patients were similar to previous reports . The mean AST to ALT ratio was less than 1 as expected, and in 96.2% this ratio was below 2. In alcoholic liver disease, this ratio is usually above two, averaging from 2.6 to 2.85 [24, 27, 28].
We observed dyslipidemia in 75.5% of our patients. Others have reported similar prevalences (20–80%) [9–12, 20, 21]. The ultrasonographic findings, such as fatty infiltration, are usually nonspecific .
It is not usually advisable to make a diagnosis of NASH before liver biopsy. The possibility of making an erroneous diagnosis is higher in NASH as compared to alcoholic liver disease. In our study, from 74 patients selected on clinical basis, 53 ones had NASH on liver biopsy. This figure is larger than the ones mentioned in other studies [30–33], which is probably due to precise patient selection in the present study, exclusion of cases with low aminotransaminase levels, or positive markers for viral hepatitis.
Factors affecting the pathogenesis of NASH are steatosis, inflammation, and fibrosis [2, 34–38]. The severity of steatosis was similar to other reports. Also, the majority of patients had portal inflammation. The findings on liver biopsy were not correlated to liver enzymes, thus the increase in liver enzymes does not seem a good estimate of the severity of liver disease.
NASH can cause fibrosis and progress to cirrhosis. It has been shown that this progress is seen in 8–26% of patients [6, 8, 9, 19]. Hepatic fibrosis, Mallory hyaline, or ballooning degeneration are findings that indicate higher likelihood of progression to cirrhosis . Altogether, these findings further underscore the importance of NASH and the need to diagnose it before it causes irreversible liver damage.
The epidemiology and risk factors of nonalcoholic steatohepatitis might be different in societies with lower rate of alcohol consumption, although this is just a preliminary hypothesis that should be evaluated in further studies. Regarding the considerable prevalence of the disease, confinement of the diagnosis to some specific epidemiologic and demographic subgroups does not seem so reasonable, particularly in regions where the distribution of the disease is not well-known.
The authors appreciate the indefatigable efforts and adroit help of Arash Etemadi, MD, and Alireza Moayyeri, MD, in this study.
- Sheth SG, Gordon FD, Chopra S: Nanalcoholic steatohepatitis. Ann Intern Med. 1997, 126: 137-45.View ArticlePubMedGoogle Scholar
- Brunt EM, Janney CG, Di Bisceglie AM, et al: Nonalcoholic steatohepatitis:a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999, 94: 2467-74. 10.1016/S0002-9270(99)00433-5.View ArticlePubMedGoogle Scholar
- Clark JM, Brancati FL, Diehl AM: Nonalcoholic fatty liver disease. Gastroenterology. 2002, 122: 1649-57.View ArticlePubMedGoogle Scholar
- Flack-ytter Y, McCullough AJ, Younossi Z, et al: Clinical features and natural history of Nonalcoholic Steatosis Syndromes. Sem Liver Disease. 2001, 21: 17-26. 10.1055/s-2001-12926.View ArticleGoogle Scholar
- Kumar KS, Malet PF: Nonalcoholic steatohepatitis. Mayo Clin Proc. 2000, 75: 733-39.View ArticlePubMedGoogle Scholar
- Angulo P: Nanalcoholic fatty liver disease. N Engl J Med. 2002, 346: 1221-31. 10.1056/NEJMra011775.View ArticlePubMedGoogle Scholar
- Reid AE: Nonalcoholic steatohepatitis. Gastroenterology. 2001, 121: 710-723.View ArticlePubMedGoogle Scholar
- Matteoni C, Younossi ZM, McCullough A: Nonalcoholic fatty liver disease:A spectrum of clinical pathological severity. Gastroenterology. 1999, 116: 1413-19.View ArticlePubMedGoogle Scholar
- Bacon B, Faravash MJ, Janney CG, et al: Nonalcoholic steatohepatitis: An expanded clinical entity. Gastroenterology. 1994, 107: 1103-6.View ArticlePubMedGoogle Scholar
- Powell EE, Cooksley GE, Hanson R, et al: The natural history of nonalcoholic steatohepatitis: A follow-up study of 42 patients for up to 21 years. Hepatology. 1990, 11: 74-80.View ArticlePubMedGoogle Scholar
- Lee RG: Nonalcoholic steatohepatitis: A study of 49 patients. Hum Pathol. 1989, 11: 594-8.View ArticleGoogle Scholar
- Ludwig J, Viggiono TR, McGill DB, et al: Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980, 55: 342-8.Google Scholar
- Propst A, Propst T, Judmaei G, et al: Prognosis in nonalcoholic steatohepatitis (letter). Gastroenterology. 1995, 108: 1607-View ArticlePubMedGoogle Scholar
- el-Hassan AY, Ibrahim EM, al-Milhim FA, et al: Fatty infiltration of the liver: analysis of prevalence, radiological and clinical features and influence on patient management. Br J Radiol. 1992, 65: 774-8.View ArticlePubMedGoogle Scholar
- Nonomura A, Mizukami Y, Unoura M, et al: Clinicopathologic study of alcohol-like liver disease in non-alcoholics; Non-alcoholic steatohepatitis and fibrosis. Gastroenterol Jpn. 1992, 27: 521-PubMedGoogle Scholar
- Baldrige AD, Perez-Atayde AR, Graeme-Cook F, et al: Idiopathic steatohepatitis in childhood: A multicenter retrospective study. J Pediatr. 1995, 127: 700-View ArticleGoogle Scholar
- Moran JR, Ghishan FK, Halter SA, et al: Steatohepatitis in obese children: A cause of chronic liver dysfunction. Am J Gastroenterol. 1983, 78: 374-PubMedGoogle Scholar
- Wanless IR, Lentz JS: Fatty liver hepatitis (Steatohepatitis) and obesity: An autopsy study with analysis of risk factors. Hepatology. 1990, 12: 1106-View ArticlePubMedGoogle Scholar
- Itoh S, Yougel T, Kawagoe K: Comparison between nonalcoholic steatohepatitis and alcoholic hepatitis. Am J Gastroenterol. 1987, 82: 650-PubMedGoogle Scholar
- Diehl AM, Goodman Z, Ishak KG: Alcohol-like disease in nonalcoholics. Gastroenterology. 1988, 95: 1056-View ArticlePubMedGoogle Scholar
- Pinto HC, Baptista A, Camilo ME, et al: Nonalcoholic steatohepatitis. Clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Dig Dis Sci. 1996, 41: 172-View ArticlePubMedGoogle Scholar
- Hamwi GJ: Therapy: Changing dietary needs. In: Diabetes Mellitus: Diagnosis and Treatment. Edited by: Danowski TS. 1964, New York, NY, American Diabetes Association, 73-78.Google Scholar
- Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001, 285: 2486-97.
- Cello JP, Grendell JH: The liver in systemic conditions. In: Hepatology. Edited by: Zakim D, Boyer TD. 1990, Philadelphia, WB Saunders, 1428-Google Scholar
- Capron JP, Delamarre M, Dupas JL, et al: Fasting in obesity: another cause of liver injury with alcoholic hyaline?. Dig Dis Sci. 1982, 54: 374-7.Google Scholar
- Adler M, Schaffner F: Fatty liver hepatitis and cirrhosis in obese patients. Am J Med. 1979, 67: 811-9.View ArticlePubMedGoogle Scholar
- Sorbi D, Boynton J, Lindor KD: The ratio of aspartate aminotransferase to alanine aminotransferase: Potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol. 1999, 94: 1018-10.1016/S0002-9270(99)00061-1.View ArticlePubMedGoogle Scholar
- Cohen JA, Kaplan MM: The SGOT/SGPT ratio – an indicator of alcoholic liver disease. Dig Dis Sci. 1979, 24: 835-View ArticlePubMedGoogle Scholar
- Lonardo A, Bellini M, Tondelli E, et al: Nonalcoholic steatohepatitis and the "bright liver syndrome": Should a recently expanded clinical entity be further expanded?. Am J Gastroenterol. 1995, 90: 2072-PubMedGoogle Scholar
- Van Ness MM, Diehl AM: Is liver biopsy useful in the evaluation of patients with chronically elevated liver enzymes?. Ann Intern Med. 1989, 111: 473-View ArticlePubMedGoogle Scholar
- James OF, Day CP: Nonalcoholic steatohepatitis (NASH): a disease of emerging identity and importance. J Hepatol. 1998, 29: 495-501. 10.1016/S0168-8278(98)80073-1.View ArticlePubMedGoogle Scholar
- Neuschwander-Tetri BA, Bacon BR: Nonalcoholic steatohepatitis. Med Clin North Am. 1996, 80: 1147-66.View ArticlePubMedGoogle Scholar
- Nomura F, Ohnishi K, Ochiai T, et al: Obesity-related Nonalcoholic fatty liver:CT features and follow-up studies after low-calorie diet. Radiology. 1987, 162: 845-7.View ArticlePubMedGoogle Scholar
- Acosta D, Wenzel DG: Injury produced by free fatty acids to lysosomes and mitochondria in cultured heart muscle and endothelial cells. Atherosclerosis. 1974, 20: 417-View ArticlePubMedGoogle Scholar
- Dianzani MU: Hepatotoxicology. In: Biochemical aspects of fatty liver. Edited by: Meeks RG, Harrison SD, Bull RJ. 1991, Boca Raton, CRC, 327-Google Scholar
- Lombardi B: Fatty liver: Considerations on the pathogenesis of fatty liver. Lab Invest. 1966, 15: 1-PubMedGoogle Scholar
- Cortez-Pinto H, Chatham J, Chacko VP, et al: Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: A pilot study. JAMA. 1999, 282: 1659-10.1001/jama.282.17.1659.View ArticlePubMedGoogle Scholar
- Berson AD, Beco V, Lettetan P, et al: Steatohepatitis-inducing drugs cause mitochondrial dysfunction of lipids peroxidation in rat hepatocytes. Gastroenterology. 1998, 114: 764-View ArticlePubMedGoogle Scholar
- Falk-ytter Y, McCullough AJ, Younossi J, et al: Clinical features and natural history of nonalcoholic steatosis syndromes. Sem Liver Disease. 2001, 21: 17-26. 10.1055/s-2001-12926.View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/3/27/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.