Background: Fatty liver is a common and generally benign condition characterized by significant lipid deposition in liver cells. It is commonly associated with alcohol or metabolic syndromes. Despite the incredible advancement in modern pharmacotherapy, there is dearth of liver centric drugs in terms of safety, efficacy, remission of disease, and adverse effects which grossly suggest the constraint in its management. Many single Unani drugs are claimed to be effective in the management of Tashshahmul Kabid which closely resembles fatty liver. The objective of the present study was to evaluate the safety and efficacy of Afsanteen in Fatty liver cases on scientific parameters.
Material and methods: A prospective parallel randomized single blind controlled trial was conducted in 36 diagnosed cases of fatty liver which were randomly assigned after obtaining voluntary informed consent into two groups; 24 cases in test and 12 in placebo control group (Cases analyzed: 20 and 10 respectively). Test drug containing 4.5 g Afsanteen was administered in capsule form twice daily for a period of 45 days, while in control group, placebo was given in similar dosage form and duration. All the cases were followed up every 15th day for subjective assessment and objective parameters at baseline and at the end of trial.
Results: The test formulation used exhibited statistically significant reduction (P < 0.05) at 45th day with respect to 0 day in the test group, while between group comparisons revealed insignificant differences (P > 0.05).
Conclusion: The study had revealed that the test drug Afsanteen has the potential to relieve some subjective and objective symptoms of Fatty liver with no adverse effects.
Keywords: Su’ Mizaj Kabid; Tashshamul Kabid; Fatty liver; Afsanteen; Unani medicine.

INTRODUCTION

Fatty liver refers to a varied scale of liver injury, extending from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. It has become a significant medical condition which is generally resulted from its ability to progress to cirrhosis and liver failure and its common manifestation in general populace. Up to 10% of cirrhotic alcoholic fatty liver may develop hepatocellular carcinoma. Apart from alcohol and metabolic syndrome, nutritional viral, and toxic factors have also been implicated (Munjal et al., 2012; Longo et al., 2012; Walker et al., 2014; Dooley et al., 2011). The estimated prevalence of Fatty liver in the Unites States and Europe ranges from 14% to 20%; (Longo et al., 2012)while the prevalence in Asia is around 12-24%, (Chitturi et al., 2007) 24.5% in asymptomatic coastal eastern Indian population (Singh et al., 2004) and 22% as detected by ultra-sonogram in the present study (Ahmed and Siddiqui, 2014).
The liver may be afflicted with all types of Su’ mizaj (~ derangement of temperament), Amraze tarkeeb (~structural diseases), and Amraze tafarruq eittisaal (~diseases of discontinuity). The Mizaj (~temperament) of liver is hot and moist; (Tabri, 1997; Ibn Rushd, 1987; Khan, 2011; Jurjani, 2010) due to erratic dietary habits, excessive consumption of fatty food etc, its mizaj is altered to barid (~cold), which is antagonistic to the liver, thereby allowing the accrual of morbid matter in the form of Tashshahmul kabid (~fatty liver) which affects the normal working of liver causing in Su’ mizaj barid kabid (~altered cold temperament of liver). Sometimes the temperament of liver may be altered to haar (~hot) due to excessive intake of hot food, drinks, drugs notably alcohol, regimens etc which disturbs the normal functioning of liver resulting in Su’ mizaj haar kabid (~altered hot temperament of liver) (Khan, 2011; Jurjani, 2010; Ibn Sina, 2010; Shah, 1997; Ahmed et al., 2014).
Many Unani drugs are claimed to be effective in the management of Su’ mizaj haar/barid kabid. Hence it has been proposed to therapeutically evaluate the safety and efficacy of Afsanteen in fatty liver cases, because it possess Musakkhin (~calorifacient), Muattir (~aromatic), Muhallil (~anti-inflammatory), Mushtahi(~appetizer), Mufatteh sudad (~deobstruent), and Muqawwi (~tonic) properties which are essential to restore Tabai mizaj (~physiological temperament) of liver (Khan, 2011; Ibn Sina, 2010; Ibn Baitar, 2000; Said, 1997; Prajapati, 2009).

MATERIALS AND METHODS

The trial was a prospective randomized single blind controlled study and approved by the Institutional ethical committee of N.I.U.M, Bangalore vide ref no: NIUM/IEC/2011-12/005/Moal/05 dated 18.04.12 and was executed from February 2013 to December 2013 at N.I.U. M. hospital (Ahmed and Siddiqui, 2014). Cases were randomly assigned to two groups (Test -24 and Control – 12) after obtaining voluntary informed consent. 36 participants were enrolled out of which 30 completed the trial (Figure-1). The duration of protocol therapy was 45 days with follow ups on 15th, 30th and 45th day. The criteria for selection of cases was mainly based on ultra- sono graphic finding of fatty liver (Mild /Grade I & Moderate/Grade II) and efficacy of the trial drugs was assessed on the basis of clinical parameters and laboratory investigations used for the purpose. Test or placebo control drug was administered in a dosage of three 750 mg capsules twice daily (4.5 g) ([Ibn Baitar, 2000; Najmul Ghani, 2010) after food with water for a period of 45 days. No concomitant treatment for fatty liver was allowed during the entire study period. The study was GCP compliant.
The criteria for selection of cases include
Patients of both gender in 20 – 60 years of age group with BMI >18.5 to <35, Diagnosed case of fatty liver (Mild /Grade I and Moderate /Grade II) by ultra – sonogram of abdomen without apparent concomitant liver disease, With/Without clinical sign and symptoms like Anorexia, Nausea, Dyspepsia, Fatigue, Dull ache/Heaviness in right hypochondriac region and Hepatomegaly, Both Alcoholic and Non-alcoholic fatty liver, Hyper lipidemic/Normolipidemic, Non diabetic/ NIDDM (Type 2 diabetes) with FBS <200 mg/dl. Exclusion criteria Pregnant and lactating women, Non-compliant patients or who failed to turn for follow up, Positive Hepatitis markers, Patients suffering from Cardiopulmonary, Renal, Neurological and Psychiatric disorders and other systemic diseases, History or presence of malignancy, Patients receiving treatment with drugs such as estrogen, corticosteroids, sodium valproate, ketoprofen, tamoxifen etc. Investigations Laboratory investigations viz; Blood, Urine and Ultra sonogram of whole abdomen were carried out at baseline and on completion of trial following standard procedures. The severity of fatty liver was based on carol Mittelstaedt grading. The radiologist was blinded to the trial. Dietary advice and life style modification Patients were advised strictly to refrain from consumption of alcohol, high carbohydrate, high fat content diet and advised to perform brisk walking daily for 45 minutes in both the groups, compliance of which was recorded daily by the patient in the compliance chart given at every visit and returned duly filled at every follow up. Statistical analysis Statistical analysis of the data was carried out using Student t test (two tailed, independent) for between group on metric parameters, Student t test (two tailed, dependent) for within each group and Fisher Exact test to find the implication of study factors on categorical scale between groups. P value < 0.05 was considered to be significant.

RESULTS

The demographic data of the trial participants are depicted in Table–1. 36 cases were registered under the trial of which 30 cases completed the study and 6 cases were lost to follow-ups. Among the cases which completed the trial, 20 belong to test group and 10 cases to control group (Table 1 & Figure 1). Patients of either gender participated in the trial (Male 70% & Female 30%). Maximum numbers of patients (85%) were in the age group of 31-50 years. Analysis of data revealed that majority of the patients had chronicity < 6 months (Table-1). Eighty percent of the cases had less than 6 months duration of illness (Table 1) which ascertained that majority of the subjects studied were of simple steatosis as also evident by scan findings of mild grade fatty liver and normal transaminases (Walker et al., 2014). BMI of 23.1 – 29.9 was observed in majority of the cases (67.5%) which is a strong risk factor for the development of Non-alcoholic fatty liver disease. 80% of the patients treated had no history of alcohol intake (Table 1). Damavi Mizaj was predominant (57.5%) among the patients who underwent the trial. 35.% of the patients had Balghami Mizaj while Saudavi Mizaj was observed in 7.5% of the patients (Table-1). The presence of fatty liver disease predominantly in Damavi Mizaj (sanguine temperament) and Balghami (phlegmatic temperament) patients suggests that those with robust built and colder temperament are more susceptible to fatty liver which substantiates the claim made by Unani physicians. Predominantly dull ache/heaviness in right hypochondriac region was observed at baseline in almost 75% of cases in test and in all the cases (100%) in control group (Table 2). The data has also revealed that the mean body weight was 76 kg. Moderate improvement in body weight was observed with the test drug (Table-2). All patients enrolled from both the groups had positive findings of fatty liver. However no any fatty liver changes improvement was observed in both the groups on pre and post assessment treatment period. Liver size was measured using ultrasonic probe and assessed at before and after trial in both the groups (Table 2). Most patients with NAFLD are asymptomatic. Diagnosis most often follows incidental detection of raised liver enzymes or of fatty liver on ultrasound (Ahmed et al., 2014). The laboratory parameters were within normal range except serum triglycerides which was considerably raised in test group. The safety parameters were also maintained throughout the course of trial in both the groups (Table 3 & 4).

Table 1. Demographic data. Click here to view full image

Table 2. Effect of treatment on Dull ache, Body weight, USG findings and Liver size (cms) in both groups studied. Click here to view full image

Table 3. Effect on LFT & S. Triglycerides in both groups studied. Click here to view full image

Table 4. Effect on safety parameters in both groups studied. Click here to view full image

Figure 1. CONSORT 2010 flow diagram. Click here to view full image

DISCUSSION

Fatty liver (FL) is an acquired reversible disorder of metabolism resulting in an accumulation of triglycerides within the hepatocytes (Subburao et al., 2003). A number of injurious agents are capable of disrupting the metabolic processes which include excessive dietary fat, alcohol ingestion, obesity, diabetes, volatile solvents, drugs, chemicals, and some poisons (Crowley, 2007).
The absence of Anorexia, Nausea, Dyspepsia in maximum cases (80%) demonstrate that fatty liver is mostly asymptomatic as stated by various studies (Munjal et al., 2012; Longo et al., 2012; Walker et al., 2014; Dooley et al., 2011; Kumar et al., 2005; Leeuwen et al., 2000; Goldman and Ausiello, 2008; Kelley et al., 1989; Boyers et al., 2011; Tierney et al., 2010; Feldman et al., 1998). These symptoms are caused due to the weakness of quwwate hazima (faculty of digestion), which further weakens the faculties in liver.
Predominantly dull ache/heaviness in right hypochondriac region was observed at baseline in almost 75% of cases in test and in all the cases (100%) in control group. However at the end of trial, 70% improvement was observed in test group which is highly significant statistically (p<0.001) while only 30% relief was observed in control group (p<0.05)(Table 2). Mild ache over hepatic region is a feature of Su’ mizaj barid kabid (Tabri, 1997; Ibn Rushd, 1987; Khan, 2011; Jurjani, 2010; Ibn Sina, 2010; Razi, 2000; Qamri, 2008; Baghdadi, 2004) which was subsided with the administration of test drug as it possess Musakkhin and Muqawwi properties. The outcome is consistent with the literature findings (Khan, 2011; Ibn Baitar, 2000; Said, 1997; Prajapati, 2009; Najmul Ghani, 2010). Highly significant weight reduction was observed in test group (p<0.001), whereas statistical significance was detected in control group cases (p<0.05) (Table 2). The outcome was in accordance with most of the studies carried where lifestyle intervention was the mainstay of treatment (Henry et al., 2007; Promrat et al., 2010; George et al., 2009; Grattagliano, 2007). There might be no biochemical evidence of liver disease as stated by Kumar V et al., 2005. Laboratory values may be normal in up to 80% of persons with fatty liver (Table 3) according to Tierney et al., (2010). Non elevation of transaminases suggest that majority of the cases treated were of simple hepatic steatosis (Aslam et al., 2015; Walker et al., 2014). All the patients enrolled had positive findings of fatty liver. In test group 85% of patients had grade I and 15% had grade II FL changes while at the end of trial, grade I FL changes were observed in 95% cases, 0% had grade II changes and 5% of case had no fatty liver, but sans statistical significance (p>0.05). However no any fatty liver changes improvement was observed in control group on pre and post assessment trial period (P>0.05) (Table 2). The plausible basis for non-resolution of fat from hepatocytes may be short duration of study and limited sample size.
However a constraint of this study was that the diagnosis of fatty liver was based on liver ultrasonography. Conversely, ultrasonography is by far the most common method of diagnosing fatty liver in clinical practice and has a fair sensitivity (87%) and specificity (94%) in detecting hepatic steatosis (Mathiesan et al., 2002). It is simple to perform, non-invasive, cost effective and does not entail any radiation hazard, and could also be used in the epidemiological studies (Nigam et al., 2013).
Liver size was measured using ultrasonic probe and assessed at before and after trial in both the groups. The Mean±SD before treatment in test group was 14.74±0.89, while after treatment it reduced to 14.20±0.31 with strong statistical significance (p<0.007) (Table 2). The statistical reduction in liver size could be attributed to the effect of test drug as it possess Musakkhin, Muhallil, Mufatteh sudad and Muqawwi kabid properties as quoted by Ibn Baitar, 2000; Said, 1997; Prajapati et al., 2009; and NajmulGhani, 2010 apart from the role of intervention of certain life style changes adopted in this study (Henry et al., 2007; Promrat et al., 2010; George et al., 2009; Grattagliano, 2007). Serum Triglycerides level was also assessed in both the groups at baseline and after the trial. In test group the Mean ± SD before treatment was 240.25±91.51, while after treatment it reduced to 202.60±77.32 with high statistical significance (p<0.01) (Table 3). Fatty liver is mainly concerned with triglycerides accumulation which was considerably raised in this study. Hypertriglyceridemia is observed in 20% to 80% of patients as quoted by Munjal et al. (2012). The test drug has the potential to reduce fat due to its Musakkhin, Muhallil and Mufatteh sudad property (Ibn Baitar, 2000; Said, 1997; Prajapati, 2009; NajmulGhani, 2010). The maintenance of laboratory investigations throughout the course of study attests that the test drug may be safe for the patients (Table 3, 4). The outcome as to its safety may also be corroborated with the experimental toxicity study of Muto et al. (2004). There are no approved therapies for fatty liver. The proper dosing, duration of treatment, safety and tolerability of these treatments is still evolving as quoted by Munjal et al. (2012). Conventional treatment for fatty liver is limited and has potentially life threatening side effects as stated by Verma et al. (2007). There is emerging and convincing evidence that worsening grades of NAFLD can progress to cirrhosis and end stage liver disease and projected to be the leading cause of liver transplantation by 2020, furthermore, associated with an increased cardio metabolic risk according to Munjal et al. (2012) and Bhatia et al. (2012) studies, has role in pathogenesis of metabolic diseases, type2 DM, and CVD as per Stefan et al. (2011) study. The efficacy of the drug as to its hepatoprotective activity was also testified by some clinical studies of Anwar et al. (1998) and Aziz et al. (2008) in similar liver disorders, pre-clinical studies of Amat et al., 2010; Kharoubi et al., 2008 and drug review studies by Govind et al. (2011) and Ahmad et al. (2010) which validates the claim of classical literature. However some limitations are inherent in this study which include; small sample size, short duration of study, inclusion of both alcoholic and non-alcoholic cases, both diabetic and non-diabetic cases, non-inclusion of lipid profile, lack of CT liver attenuation values (Aslam et al., 2015), lack of reliable diet chart. Hence further studies are imperative with modified methodology to limit these inadequacies for wider reliability and acceptability. CONCLUSION

The trial demonstrated that the test drug Afsanteen has significant effect in relieving dull ache from the right hypochondriac region, in reducing body weight, liver size, and triglycerides levels when compared to control drug. With all these qualities, the Unani test formulation may be considered as a safe and effective remedy in the treatment of fatty liver.

ACKNOWLEDGEMENT

This being an institutionally funded study, the author acknowledges all the staff of National Institute of Unani Medicine, Bangalore, India and the trial participants for their support, consent and cooperation. The authors gratefully acknowledge Dr. K.P. Suresh (Biostatistician) for his contribution to statistical analysis of the data.

CONFLICT OF INTEREST

None declared.

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