Year : 2010 | Volume
: 53 | Issue : 3 | Page : 408--413
Comparison of clinical, biochemical and histological features of alcoholic steatohepatitis and non-alcoholic steatohepatitis in Asian Indian patients
Deepak Kumar Singh1, Archana Rastogi1, Puja Sakhuja1, Ranjana Gondal1, Shiv Kumar Sarin2,
1 Department of Pathology, G B Pant Hospital, Delhi, India
2 Department of Gastroenterology, G B Pant Hospital, Delhi, India
Deepak Kumar Singh
597, Z - Type Flats, Lucknow Road, Timarpur, Delhi - 110 054
Background: Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) are significant forms of liver disease and may progress to end-stage liver disease, cirrhosis and potentially malignant complications. The most difficult aspect of establishing a diagnosis of NASH is distinguishing it from ASH. Laboratory markers such as AST, ALT and GGT lack sufficient sensitivity and specificity. Aim: To study the clinical, biochemical and histological differences between non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH). Materials and Methods: Sixty histologically confirmed cases of non-alcoholic steatohepatitis and 38 cases of alcoholic steatohepatitis were included in the study. A modified form of scoring system proposed by Yip and Burt was used to grade histological features of NASH and ASH. Results: Mean age was 42.85 ± 12.36 years in ASH group and 35.07 ± 8.06 years for NASH group. Male: Female ratio was 37:1 in ASH and 4:1 in NASH. The mean ALT (P = 0.012), SAP (P = 0.003), serum bilirubin (P = 0.001), AST/ALT ratio (P = 0.03), steatosis (P < 0.001), ballooning degeneration of hepatocytes (P < 0.001), portal inflammation (P < 0.001), Mallory hyaline (P = 0.001), ductular proliferation and fibrosis (P < 0.001) showed a significant difference between ASH and NASH cases. Discussion: Older age, male sex, larger derangement of serum biochemistry, high serum bilirubin, AST/ALT > 1, more ballooning degeneration, portal inflammation, Mallory«SQ»s hyaline, hepatocytic and ductular cholestasis, ductular proliferation and higher stage of fibrosis favors a diagnosis of ASH. Younger age, high ALT, AST/ALT < 1, higher grade of steatosis and absence of extensive neutrophilic portal inflammation favors a diagnosis of NASH.
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Singh DK, Rastogi A, Sakhuja P, Gondal R, Sarin SK. Comparison of clinical, biochemical and histological features of alcoholic steatohepatitis and non-alcoholic steatohepatitis in Asian Indian patients.Indian J Pathol Microbiol 2010;53:408-413
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Singh DK, Rastogi A, Sakhuja P, Gondal R, Sarin SK. Comparison of clinical, biochemical and histological features of alcoholic steatohepatitis and non-alcoholic steatohepatitis in Asian Indian patients. Indian J Pathol Microbiol [serial online] 2010 [cited 2020 Oct 26 ];53:408-413
Available from: https://www.ijpmonline.org/text.asp?2010/53/3/408/68246
Alcoholic steatohepatitis (ASH) occurs due to excessive alcohol consumption with alcohol acting as a direct hepatotoxin. [1, 2] Spectrum of alcoholic liver disease ranges from steatosis to steatohepatitis (alcoholic steatohepatitis) to cirrhosis. Steatosis, ballooning degeneration of hepatocytes and lobular inflammation, either mixed type or with a predominance of neutrophilic polymorphs, with or without fibrosis are the most common histologic features seen in alcoholic liver disease. ,
In 1980, Ludwig et al.  described an alcoholic hepatitis-like pattern of injury in the liver of non-alcoholic patients. They introduced the term 'non-alcoholic steatohepatitis' (NASH) to describe this disease entity. The histologic features characteristic of steatohepatitis in the absence of significant alcohol consumption can be seen in a wide variety of conditions like drugs and toxins exposure, Wilson's disease Indian childhood cirrhosis, jejuno-ileal bypass, obesity surgery, massive intestinal resection, fasting, cachexia, bulimia, parentral nutrition in adults, intravenous glucose in last week before death, jejunal diverticulosis, abetalipoprotenemia and insulin resistance syndromes (familial, lipodystrophies, polycystic ovary syndrome and acquired insulin resistance (metabolic) syndrome). The last entity i.e. acquired insulin resistance syndrome (metabolic syndrome) is regarded the most important causal factor for 'non-alcoholic steatohepatitis' or 'idiopathic' non-alcoholic steatohepatitis (NASH). Histologic features most commonly found in NASH are steatosis, ballooning degeneration of hepatocytes and lobular inflammation with or without fibrosis.  NASH is a histologic diagnosis and can be diagnosed only on liver biopsy.
Both ASH and NASH are significant forms of liver disease and may progress to end-stage liver disease, cirrhosis, and its attendant physiologic, metabolic, and potentially malignant complications. Hepatocellular carcinoma is a recognized complication of both entities. Both diseases may necessitate liver transplantation, and have been reported to recur in the allograft livers. ,,,
The most difficult aspect of establishing a diagnosis of NASH is distinguishing it from ASH. Correct diagnosis of NASH versus ASH is necessary as it has important therapeutic and prognostic implications for the patient. Studies show that laboratory markers such as AST, ALT and GGT lack sufficient sensitivity and specificity to diagnose chronic excessive alcohol consumption. , One of these studies has, however, shown that AST/ALT ratio can predict ASH.  Many of the histologic features that characterize ASH and NASH in adult patients are similar, regardless of the initiating pathogenetic event.  A detailed history of alcohol should be obtained from patient, family members and the primary care provider if NASH or ASH is suspected but in cases clinically suspected and classified as NASH there might be spurious use of alcohol leading to wrong categorization of patient.
The present study was conducted to study the similarities and differences in clinical and histologic features between NASH and ASH, which may help in differentiating the two disease entities. In this study we studied clinical features, liver histology and liver function tests which are routinely performed in any patient presenting with liver disease and are available at a primary care center.
Materials and Methods
Sixty cases of non-alcoholic steatohepatitis and 38 cases of alcoholic liver disease have been included in the study. The duration of the study was two years from January 2007 to December 2008
The presenting symptoms in patients with NASH were (in decreasing order of frequency): fatigue, upper abdominal discomfort, bloating, anorexia, lethargy and hepatomegaly. Some patients were incidentally detected by raised transaminases. If the patient presented with the above symptoms to our Gastroenterology department and on liver function tests was found to have raised aminotransferases, he/she was exhaustively investigated for NASH. Patients were included in NASH group if they had elevated serum transaminases, no history of alcohol intake (alcohol intake < 20 gm/day) and presence of fatty liver on USG/MRI. The morphologic criteria for including cases were the same as those given by Matteoneoi et al.  for classifying liver biopsy as NASH i.e. presence of any degree of steatosis, ballooning and lobular inflammation with or without fibrosis. Exclusion criteria included concurrent viral infection, autoimmune hepatitis, hemochromatosis, Wilson's disease, overt diabetes at first presentation, concurrent systemic illness and concurrent medications such as high dose estrogens, corticosteroids, and amiodarone in the last six months. ,
The inclusion criteria for including patients in the alcoholic liver disease group were - confirmed and continuous use of significant amount of alcohol, defined as > 80 gm per day for the last five years and abnormal serum transaminases with or without clinical evidence of alcoholic liver disease like jaundice, hepatomegaly, ascitis, esophageal varices, spider nevi and palmar erythema. The morphologic criteria for including cases as alcoholic steatohepatitis were steatosis or lobular inflammation either mixed or comprising predominantly of polymorphs with or without fibrosis.  Exclusion criteria included concurrent viral infection, concurrent medications such as high dose estrogens, corticosteroides, and amiodarone in the last six months or other co-morbid condition. 
Viral hepatitis was excluded by negative serology for hepatitis B virus (HBsAg, anti-HBe, HBV DNA), hepatitis C virus RNA (HCV RNA) by RT-PCR and antibodies to hepatitis C virus (anti-HCV). Autoimmune hepatitis was excluded by testing for elevation of anti-nuclear antibody (ANA), anti smooth muscle antibody (ASMA) and Liver/Kidney Microsomal antibodies (LKM) greater than 1:80 and/or consistent histology. Diabetes and impaired glucose tolerance was diagnosed as defined by WHO criteria.  Diabetes Mellitus was diagnosed if the fasting plasma glucose was > 126 mg/dL or if two-hour value of blood glucose level was > 200 mg/dL during glucose tolerance test Wilson's disease was excluded by absence of Kayser-Fleischer rings (KF rings) on slit-lamp examination and measurement of serum ceruloplasmin and urinary copper estimation.
Case files of patients were reviewed and all clinical and laboratory data was recorded. Serial sections of liver biopsies were cut and stained with hematoxylin and eosin, Masson's trichrome, reticulin silver stain and orcein. The presence of Mallory's hyaline was confirmed by immunohistochemistry for Ubiquitin (Ubiquitin, DBS, USA, Chromogen - DAB) in all cases of ASH and NASH. Immunostaining for cytokeratin - 7 (CK - 7, Novocastra, USA, Chromogen - DAB) was performed in all liver biopsies to assess bile ductular proliferation.
For grading histological features of liver biopsies in both NASH and ASH groups a modified form of the scoring system proposed by Yip and Burt (2006)  was used. The scoring system of Yip and Burt was proposed for ASH. In this system, steatosis, lobular inflammation, cell death and ballooning degeneration were scored individually with stage of biopsy recorded separately. Other parameters like Mallory's hyaline, lipogranuloma and portal inflammation were recorded as present or absent.
All clinical, biochemical and histological features were compared between the two groups. Comparison of gender distribution between two groups was done by Pearson χ2 test. Student's t-test and Mann-Whitney test were used for comparing parametric and non-parametric data respectively. For comparing histological features between groups Pearson χ2 test and Fisher's Exact Test was used. All results are expressed as mean ± SD or as number (percentage). A P value < 0.05 was considered statistically significant.
Clnical and Biochemical Parameters in Ash0 and Nash0
We compared clinical, biochemical and histologic features between 60 cases of non-alcoholic steatohepatitis and 38 cases of alcoholic steatohepatitis. The differences in clinical and biochemical features between ASH and NASH are given in [Table 1]. Mean age was 42.85 ± 12.36 years (range 20-70) for alcoholic steatohepatitis (ASH) group and 35.07 ± 8.06 years (range 9-57) for non-alcoholic steatohepatitis (NASH) group. Mean age in NASH patients was significantly lower than ASH group (P = 0.001). Male: Female ratio was 37:1 in ASH and 4:1 in NASH. Out of 60 patients of NASH, five (8.33%) patients had diabetes mellitus, 16 (26.67%) were mildly obese, 29 (48.33%) were moderately obese and 10 (16.67%) had hypertriglyceridemia. The mean ALT and SAP was higher in NASH patients (NASH vs. ASH; ALT - 110.82 ± 40.99 IU/mL vs. 79.69 ± 66.49 IU/mL, P = 0.012; SAP - 203.5 ± 97.12 IU/mL vs. 118.09 ± 62.34 IU/mL, P = 0.003). Serum bilirubin and AST/ALT ratio was higher in ASH patients (NASH vs. ASH; Bilirubin - 1.47 ± 0.97 mg% vs. 5.12 ± 7.67 mg%, P = 0.001; AST/ALT - 0.68 ± 0.33 vs. 1.24 ± 0.81, P = 0.03). The AST/ALT ratio ranged from 0.43 to 3.13 (median - 1.14) in ASH cases and 0.3 to 2.94 (median - 0.64) in NASH cases No significant difference was observed in AST levels between NASH and ASH groups (AST - 70.6 ± 23.67 IU/mL vs. 91.77 ± 31 IU/mL, P = 0.286).
Histologic Features in ASH and NASH
The differences in histologic features between ASH and NASH are given in [Table 2] and [Table 3] and [Figure 1]. Some salient features of ASH and NASH are given in [Figure 2] and [Figure 3]. Steatosis was present in 100% of the biopsies of NASH whereas it was observed in only 76.3% of liver biopsies of ASH. It was prominent and severe (grade 3) in 48.3% in NASH and only 13.2% of ASH (P = 0.001). NASH cases showed a higher prevalence of steatosis in zone three as compared to ASH cases (ASH vs NASH - 4/38 (10.52%) vs 24/60 (40%), P = 0.002). Ballooning degeneration of hepatocytes was severe in ASH patients compared to NASH (ASH vs. NASH, ballooning grade 2 - 71.7% vs. 28.3%; P = 0.001). Vacuolated nuclei were slightly more frequent in ASH than NASH but the difference was not significant (ASH vs. NASH - 42.1% vs. 30.2%, P = 0.409). Ductular proliferation was significantly more frequent in ASH (ASH vs. NASH - 92.1% vs. 0 %). There was no significant difference in the presence of lobular inflammation (P = 0.183). However, presence of neutrophils as a component of lobular inflammation was seen more in ASH cases (ASH vs. NASH - 31/38 (81.58%) vs. 5/60 (8.33%), P = 0.001). Moderate to marked inflammation in portal areas was more common in ASH as compared to NASH (55.3% vs 13.2%, P < 0.001). The portal inflammation in both ASH and NASH comprised of lymphocytes and in some cases neutrophils were also seen as a component of inflammation. Neutrophils were seen in the portal tracts in 36/38 (94.73%) cases of ASH and 7/60 (11.67%) cases of NASH (P = 0.001). Sclerosing hyaline necrosis was seen in 13/38 (34.21%) cases in ASH, while none of the NASH cases showed this feature. Cholestatic hepatitis was seen in 23/38 (60.52%) cases while it was not seen in any of the NASH cases. Mallory hyaline was much more frequent and prominent in ASH as compared to NASH (ASH vs. NASH - 27/38 (71.1%) vs. 12/60 (20%), P = 0.001). Apoptotic bodies were seen in 7/60 (11.67%) cases of NASH and 12/38 (31.57%) cases of ASH. Perisinusoidal fibrosis alone was noted in 37/60 (61.7%) NASH cases whereas in ASH group it was noted in 1/38 (2.69%) (P = 0.001). Cirrhosis was present in 13/38 (47.4%) cases of ASH whereas none of the NASH cases had cirrhosis.
In this study we analyzed the clinical, biochemical and histologic differences between patients with alcoholic steatohepatitis and non-alcoholic steatohepatitis. We found that of all the features compared between the two diseases, age, gender ratio, bilirubin and ALT levels, AST/ALT ratio, steatosis, ballooning degeneration, portal inflammation, Mallory's hyaline and fibrosis showed a significant difference.
The mean age in the NASH group was significantly lower than ASH group. The minimum age in the ASH group was 28 years and in the NASH group was nine years. NASH has been reported in children as young as seven to eight years.  In ASH patients a prolonged and constant alcohol intake is required for developing ASH, estimated to be about 5-10 years. On the other hand, recent changes in lifestyle like high fat in the diet and lack of exercise to which an individual is exposed right from childhood along with high prevalence of diabetes, hypertension and genetic predisposition will make NASH cases present at an earlier age. Another reason for lower age at presentation of NASH cases is that many patients are diagnosed after being worked up for incidentally detected raised transaminases. If raised transaminases are found in any patient, he or she is, in most instances, first questioned for a history of alcohol intake. If history of alcohol intake is not present the patient is investigated to rule out other diseases and then a liver biopsy is performed to confirm or rule out NASH. However if a patient presents with raised transaminases with a history of alcohol intake, then there might be reluctance for performing a liver biopsy for diagnosis of ASH unless significant morbidity is present. First advice is to stop alcohol intake. By the time the patient presents to the hospital for the second time and a liver biopsy is performed, significant time has gone and the disease is far advanced in terms of liver injury and histological changes. This makes the age of presentation of histologically confirmed cases of ASH higher as compared to histologically confirmed cases of NASH. This might also be the reason that more advanced disease is seen on liver histology in ASH cases and help us in distinguishing NASH from ASH.
The male to female ratio in our cases was higher in ASH as compared to NASH and there was a significant difference. We feel this is due to socio-economic factors in our society where the percentage of males consuming/abusing alcohol is significantly higher than females. On the other hand occurrence of NASH depends on diet and co-morbid conditions like obesity and diabetes mellitus which has a high prevalence among both males and females.  Out of 60 patients of NASH in our study, 8.33% had diabetes mellitus while none of the ASH patients had diabetes. Sugimoto et al.  also reported a higher prevalence of diabetes mellitus in NASH patients as compared to ASH.
Our study showed that bilirubin, ALT, AST/ALT ratio and SAP showed a significant difference in NASH and ASH groups. ALT and SAP was higher in NASH group and serum bilirubin and AST/ALT ratio was higher in ASH group. Although mean AST was higher in ASH group the difference was not significant. The hypertransaminasemia in NASH is ALT dominant as seen in our study. Similar findings were reported by Sugimoto et al.  The AST/ALT ratio is often said to be greater than two in cases of ASH.  In our study there was a significant difference in AST/ALT ratio in ASH and NASH cases with ASH cases having a higher ratio. This was also reported by Sorbi et al. who concluded that AST/ALT ratio is a useful index for distinguishing ASH from NASH. Values < 1 suggest NASH and values ≥ 2 strongly suggest ASH.
Our study showed some significant differences in liver histology of NASH and ASH cases. NASH is reported to be a milder disease in Indian patients.  In one study, mild, moderate and severe NASH was present in 65.5%, 12.5% and 9.35% cases respectively. Another study from our institute showed that 29.6% patients were grade 1, 36.6% were grade 2 and 33.8% were grade 3 NASH.  Presence of milder disease in NASH at the time of presentation may help in distinguishing NASH from ASH and instituting appropriate treatment. In general, the histological changes were more severe in ASH than NASH. Pinto et al.  compared the histological findings of 32 patients with NASH, 21 ambulatory alcoholic patients, and 52 hospitalized alcoholic patients. Although the histological lesions were noted to be similar, the activity was greater in the last group (hospitalized alcoholics). This is in agreement with several other investigators' comments that the lesions of NASH are typically milder than those in alcoholic patients. Steatosis was seen more in NASH cases and was of a higher grade (ASH vs. NASH - 21% vs. 80%) Morita et al. and Kojima et al. also reported similar findings. ASH cases showed more ballooning degeneration of hepatocytes, portal inflammation and Mallory's hyaline (ASH vs. NASH; ballooning grade 2 ± 71% vs. 28%; portal inflammation grade 3 ± 23.7% vs. 0%; Mallory's hyaline positive - 71.1% vs. 26.7%). Fibrosis was also more severe in ASH cases. Majority of the NASH cases (61.7%) showed perivenular and pericellular fibrosis. Fibrosis grade three (bridging fibrosis) was seen in 39.5% of ASH cases and 6.7% NASH cases. Cirrhosis was found in 34.2% of ASH cases while none of the NASH cases showed cirrhosis. In one study stage 1 fibrosis was seen in 21.8% cases, stage 2 fibrosis in 12.5% cases and stage 3 in 9.3% cases. None of the cases has cirrhosis.  Cholestatic hepatitis, bile ductular cholestasis and bile ductular proliferation was seen only in ASH cases. The bile ductular proliferation was commonly seen in expanded portal tracts and periportal areas. Ductular proliferation might be related to repeated occurrence of liver injury in ASH and associated necrotizing and fibrotic changes with disappearance of hepatocytes.  No significant difference was observed in lobular inflammation and vacuolated nuclei between ASH and NASH cases (both were seen in higher number of ASH cases but severity was more in NASH cases).
Pinto et al.  found an increasing degree of severity of hepatocellular damage, Mallory bodies, neutrophils and mononuclear infiltration, and pericellular and portal fibrosis in ASH cases while NASH cases had more steatosis and glycogenated nuclei. Itoh et al.  found significant differences in grades of nuclear vacuolation, periportal/pericellular fibrosis, proliferation of bile ductules, and changes in the shape of the portal tracts. Morita et al.  found increased ballooning of hepatocytes, lipogranuloma, focal necrosis, acidophilic bodies and fibrosis in ASH and increased steatosis and nuclear vacuoles in NASH cases. In contrast, Sugimoto et al.  did not find any significant difference in liver histology of ASH and NASH patients.
To conclude, it is important to distinguish NASH from ASH, especially in cases in which there is spurious use of alcohol or the history of alcohol is not forthcoming from the patients. It is difficult to distinguish ASH from NASH exclusively on the basis of histology. However, clinical features, biochemical parameters and liver histology taken together can differentiate ASH from NASH. Older age, male sex, larger derangement of serum biochemistry, high serum bilirubin, AST/ALT > 1, more severe overall histologic changes in liver biopsy with higher grade of ballooning degeneration, portal inflammation, Mallory's hyaline, presence of cholestatic hepatitis, bile ductular cholestasis, bile ductular proliferation, sclerosing hyaline necrosis and higher stage of fibrosis are pointers towards a diagnosis of alcoholic steatohepatitis in the absence or unavailability of history of alcohol intake. Presence of younger age, high ALT, AST/ALT < 1, milder disease on histology, higher grade of steatosis and absence of predominantly neutrophilic infiltrate in portal tracts point towards a diagnosis of non-alcoholic steatohepatitis.
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