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Probiotic Therapy in Patients with Nonalcoholic Steatohepatitis in Zagazig University Hospitals

Aim: Nonalcoholic fatty liver disease (NAFLD) is probably the most common liver disorder in the world. A subgroup of NAFLD patients is characterized by injury to the hepatocytes and inflammation in addition to excessive fat (steatohepatitis), the latter condition is nominated nonalcoholic steatohepatitis (NASH). This work aimed to evaluate the role of probiotics on the outcome of NASH in patients admitted to the Tropical Medicine Department, Faculty of Medicine, Zagazig University (inpatients and outpatients). Materials and methods: This study was performed on 30 patients (17 males and 13 females), with body mass index from 30 to 35 and average age of 44 years with bright fatty liver in ultrasonography and raised alanine transaminase (ALT) and aspartate transaminase (AST) and positive liver biopsy findings. The patients were divided into group I (case group) that included 15 patients who received probiotics and group II of 15 patients as control group who did not receive probiotics; the study was conducted between November 2014 and April 2016. Clinical assessment, laboratory evaluation, pelvic-abdominal ultrasound, and liver biopsy of all cases were carried out. Results: In this study, there was significant decrease in liver enzymes (ALT and AST) and no statistically significant other laboratory findings. Also there was relief for dyspepsia in some patients. Conclusion: Probiotics treatment is effective, safe, well-tolerated, inexpensive, appropriate for long-term use, and optimally, works at multiple levels to downregulate inflammatory mediators, and therefore, probiotics could be an option in the treatment of NASH. How to cite this article: Monem SMA. Probiotic Therapy in Patients with Nonalcoholic Steatohepatitis in Zagazig University Hospitals. Euroasian J Hepato-Gastroenterol 2017;7(1):101-106.


INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) is a state defined by extreme fat accumulation in the form of triglycerides (steatosis) in the liver (more than 5% of liver cells histologically). It is considered nowadays as one of the most frequent causes of abnormal liver tests all over the world, and it ranges from simple steatosis to advanced fibrosis and cirrhosis. A subgroup of NAFLD patients were characterized by injury to the hepatocytes and inflammation in addition to excessive fat (steatohepatitis). The latter condition, nominated nonalcoholic steatohepatitis (NASH), is practically indistinguishable histologically from alcoholic steatohepatitis, and it is characterized by fatty infiltration of the liver with different degrees of inflammation, necrosis, and fibrosis, almost identical to those of alcoholic liver disease; without significant alcohol ingestion. 1

Probiotic Therapy in Patients with Nonalcoholic Steatohepatitis in Zagazig University Hospitals Sameh M Abdel Monem
Simple steatosis seen in NAFLD does not correspond to increased short-term morbidity or mortality, but advancement of this condition to NASH noticeably increases the risks of fibrosis, cirrhosis (cryptogenic cirrhosis), liver failure, and hepatocellular carcinoma (HCC). The prevalence of NAFLD ranges from 10 to 24% of the general population, while NASH affects about 3% of the lean population and nearly half of morbidly obese people. 2 The term nonalcoholic steatohepatitis or NASH is expressing the clinical and pathological characters of NAFLD coupled with the pathological characters mostly present in alcoholic liver disease itself. This description is still proper as NAFLD can progress to cirrhosis with fat from simple steatosis, through NASH and fibrosis. 3 Nonalcoholic steatohepatitis is a chronic liver disease, i.e., earning increasing significance due to its great prevalence all over the world, the difficulty in diagnosis with noninvasive diagnostic methods, and the risk of succession to advanced fibrosis and cirrhosis, all of which make NASH difficult for doctors. Although the natural history of NASH and the causes of disease progression remain mostly unknown, more than a few data suggest that in some patients the disease may follow an indolent course until it progresses to end-stage liver disease. 4,5 Most patients have the clinical characteristics of insulin resistance syndrome, including obesity, hypertension, glucose intolerance, and typical dyslipidemia. Insulin resistance plays a role not only in obese individuals but also in lean nondiabetic patients with hepatic steatosis. 6 The "two-hit" hypothesis is the leading theory for the pathogenesis of NASH. This model suggests that the initial event or first "hit" leads to steatosis, and the second "hit" leads to necroinflammation and fibrosis. Insulin resistance has been implicated as the first "hit" and various insults, such as oxidative stress, cytokine effects, and fatty acid toxicity are suspected as potential other hits that lead to hepatocellular injury. 7 Tumor necrosis factor-alpha (TNF-α) in the liver can contribute to oxidative stress; furthermore, it may contribute to insulin resistance. 8 Additionally, TNF-α also initiates fibrosis both by direct activation of hepatic stellate cells and by stimulating production of tumor growth factor (TGF)-beta, a potent profibrogenic cytokine. 9 A complex relationship exists between endotoxins, stellate cell activation, and release of cytokines and chemokines due to increased intestinal bacterial overgrowth, increased gut permeability, and reduced endotoxin scavenging by the reticuloendothelial system. The endotoxin releases a battery of cytokines; interleukin (IL)-1, IL-6, and TNF-α from nonparenchymal cells. 10 The general belief that intestinal bacterial overgrowth has a role in NAFLD is supported by the evidence that obesity and diabetes, which are the major risk factors for NASH, are also associated with intestinal dysmotility 11 and small bowel bacterial overgrowth. 12 Probiotics are traditionally defined as viable microorganisms that have beneficial effects in the prevention and treatment of specific pathologic conditions when they are ingested. 13 There are many proposed mechanisms by which probiotics may protect the host from intestinal disorders, including production of inhibitory substances, blocking of adhesion sites, competition for nutrients, degradation of toxin receptor, and stimulation of immunity. 13 Probiotics affect intestinal bacterial flora by increase of anaerobic bacteria and decrease of the population of potentially pathogenic microorganisms. 14 This work aimed to evaluate the role of probiotics on the outcome of NASH in patients admitted to the Tropical Medicine Department, Faculty of Medicine, Zagazig University (inpatients and outpatients).

MATERIALS AND METHODS
This randomized controlled study was performed on 30 patients (17 males and 13 females), with body mass index (BMI) from 30 to 35 and average age of 44 with bright fatty liver in ultrasonography and raised alanine transaminase (ALT) and aspartate transaminase (AST) and positive liver biopsy findings. Patients were divided into group I (case group) that included 15 patients who received probiotics and group II that included 15 patients (control group) who did not receive probiotics and were consulting at Tropical Medicine Department, Faculty of Medicine, Zagazig University Hospitals between November 2014 and April 2016.

Inclusion Criteria
Patients with elevated liver enzymes and bright liver by ultrasonography were examined and investigated for selection of patients with NASH, which was proved by liver biopsy.

Exclusion Criteria
Patients with history of significant alcohol consumption more than 20 gm/day or under dietetic regimen; patients with positive hepatitis B and C virus markers; patients who were taking lipid-lowering medications, metformin, or thiazolidinediones; and patients with any other metabolic liver disease were excluded from the study. Kidney function tests were performed: For exclusion of cases with renal impairment. Compensated and decompensated cirrhotic patients; hepatic focal lesion; AST/ALT ratio >1 were also excluded.
All patients were subjected to the following: Full clinical history with stress on age and sex, change in appetite, dyspepsia, abdominal distension, right hypochondrial pain, and fatigue. Patients with history of medical diseases, e.g., diabetes mellitus, hypertension, bilharziasis, chronic viral hepatitis, pituitary disease, adrenal disease or pancreatic disease, history of surgical operation, e.g., gastric bypass or jejunoileal bypass were also excluded.
All patients were checked for parameters of general examinations, such as blood pressure, pulse, face complexion, hand and lower limb examination, body weight, height, and BMI that was defined by Kumar and Clark. 15 Local examination of abdomen and liver was accomplished.

EJOHG
Laboratory assessment included complete blood count, hemoglobin level, white blood cells, and platelets counts. Parameters of liver function tests were also checked. Imaging of abdomen and the liver was done.

Probiotic Therapy
The patients were kept on probiotic supplementation. Acidophilus capsule (Lactobacillus acidophilus, which contains 2 billion viable organism, and mixture of rice flour, gelatin, and magnesium stearate) was given to patients 30 minutes before meal three times daily for 1 month duration (Acidophilus, Swanson Health Products, USA website, www.swansonvitamins.com).

Statistical Analysis
Data were checked, entered, and analyzed using Statistical Package for the Social Sciences version 18 for Windows. Data were expressed as mean ± standard deviation for quantitative variable, number and percentage for qualitative one. Chi-squared (χ 2 ) or t-test and paired t-test were used when appropriate; p < 0.05 was considered significant; p < 0.001 was considered highly significant.

RESULTS AND DISCUSSION
Nonalcoholic fatty liver disease is probably the most common liver disorder in the world. 16 It is generally believed that NAFLD affects 2.8 to 24% of the general population and affects adults and children. 17 In addition, NAFLD is the consequence of excess triglyceride accumulation in hepatocytes in the absence of significant alcohol consumption. 18 It includes a spectrum of hepatic changes from steatosis alone, to NASH, fibrosis, cirrhosis, and even HCC. 19 Probiotics are traditionally defined as viable microorganisms that have beneficial effects in the prevention and treatment of specific pathologic conditions when they are ingested. 13 There are many proposed mechanisms by which probiotics may protect the host from intestinal disorders, including production of inhibitory substances, blocking of adhesion sites, competition for nutrients, degradation of toxin receptor, and stimulation of immunity. 13 Probiotics affect intestinal bacterial flora by increase of anaerobic bacteria and decrease of the population of potentially pathogenic microorganisms. 14 This study is aimed to evaluate the role of probiotics on the outcome of NASH in humans.
This randomized controlled study was performed on 30 patients (17 males and 13 females), with BMI from 30 to 35 and average age of 44 with bright fatty liver in ultrasonography and raised ALT and AST and positive liver biopsy findings. Patients were divided into group I (case group) that included 15 patients who received probiotics and group II that included 15 patients (control group) who did not receive probiotics and were consulting at Tropical Medicine Department, Faculty of Medicine, Zagazig University Hospitals between November 2014 and April 2016.
In the present study of demographic, clinical, and abdominal ultrasound (U/S) findings before treatment for both groups, no significant difference was seen. Also this study showed no significant difference as regards complete blood count, liver function test, kidney function test, prothrombin time (PT), international normalized ratio (INR), lipid profile, and blood sugar. Due to all patients were complaining from nonalcoholic steatohepatitis then were divided randomly into two groups.
In the present study, patients were matched with control subject as regards posttreatment biochemical findings, which showed no significant difference (Tables 1  and 2). But there was a highly significant difference in ALT and significant difference in AST. Otherwise, other biochemical changes showed no significant difference between both groups This is in agreement with the results of Solga and Diehl, 20 Loguercio et al, 21 and Portincasa et al, 22 which found similar changes in ALT and AST. These findings denote that the use of probiotics in these patients plays some role in improving the necroinflammatory status of the liver (Tables 3 to 6).      This study showed improvement of dyspepsia in group I posttreatment; otherwise, there were no significant change in other symptoms and in abdominal U/S findings.
This study also showed significant decrease in ALT and AST in group I posttreatment in comparison to pretreatment; otherwise, there was no significant change in other laboratory findings, and these were in agreement with the findings of Loguercio et al 21

CONCLUSION
Probiotics treatment is effective, safe, well-tolerated, inexpensive, appropriate for long-term use, and optimally works at multiple levels to downregulate inflammatory mediators, and therefore, probiotics could be an option in the treatment of NASH.