Clinical evaluation of a herbal formulation in liver disorders.

Introduction

The liver is the largest gland in the human body and performs a number of functions including glycogen storage, plasma protein synthesis and detoxification. Exposure to a wide variety of insults such as alcohol, drugs, chemicals, viruses and bacteria makes the liver one of the most frequently injured organs in the body. This leads to the manifestation of various liver disorders such as hepatitis, alcoholic liver disease, non-alcoholic liver disease, chronic hepatitis and liver cirrhosis. This naturally brings about impairment of vital functions of the liver leading to various clinical manifestations and biochemical abnormalities.

Liver disease is a term for a collection of conditions, diseases and infections that affect the cells, tissues, structures or function of the liver. Liver disease may range from mild to severe depending on the type of disease. Long term effects of the disease include cirrhosis of the liver, liver failure, illnesses in other parts of the body such as kidney damage or low blood counts, gastrointestinal bleeding and liver cancer.

Cirrhosis is defined histologically as a diffuse hepatic process characterised by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules. The progression of liver injury to cirrhosis may occur over weeks to years. Cirrhosis is one of the leading causes of death by disease, and the cost of cirrhosis in terms of human suffering, hospital costs and lost productivity is high. Chronic alcoholism is one of the most common causes of liver cirrhosis.

Alcoholic liver disease is a major cause of morbidity and mortality worldwide (Orholm 1985, Grant 1991). Mortality from alcoholic cirrhosis is higher than non alcoholic and survival is 5-10 years in 7-23% with 25% of patients dying within 1 year (Propst 1995, Chedid 1991). Alcohol can cause liver damage in the form of fatty liver, hepatitis, fibrosis and liver cirrhosis. Pathologic changes observed in patients with alcohol induced liver disease are categorised into alcoholic fatty liver (simple steatosis), alcoholic hepatitis and alcoholic cirrhosis.

Drugs and chemicals can cause a wide spectrum of liver injury in several ways. Some drugs are directly injurious to the liver, others are transformed by the liver into chemicals that can be injurious to the liver directly or indirectly. It is common to find liver disorders in patients exposed to medications such as antitubercular drugs, paracetamol and statins (Smith 2003). Drug induced hepatic injury is the most common reason cited for withdrawal of an approved drug. The manifestations of drug induced hepatotoxicity are highly variable, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure.

Viral hepatitis is a global public health problem, responsible for a major degree of morbidity and mortality. Viral hepatitis occurs endemically and sporadically throughout the world, depending on the endemicity of infection. Hepatitis A is an acute but benign form of viral hepatitis. Acute hepatitis B can range from sub clinical disease to fulminant hepatic failure and individuals with chronic hepatitis B are at increased risk of the development of hepatocellular carcinoma.

Early renormalisations of hepatic functions with symptomatic and clinical recovery are the objectives in the clinical management of liver disorders. At present no specific drug therapy is available to manage these liver disorders. A number of medicinal plants have been used to minimise and treat liver disorders (Bharani 1995). Herbal medicine is increasingly being validated by scientific investigations which seek to understand the active ingredient. The effectiveness of these herbal preparations needs to be clinically tested to prove their efficacy and safety.

This study was conducted to evaluate the safety and efficacy of a herbal formulation in patients with liver disorders.

Composition of the herbal formulation

Each capsule contains

              Name of the herb       Parts used    Quantity

Extracts of   Capparis spinosa       Root          49 mg
              Cichorium intybus      Seed          49 mg
              Solanum nigrum         Whole plant   25 mg
              Terminalia arjuna      Bark          25 mg
              Cassia occidentals     Seed          13 mg
              Achillea millefolium   Aerial part   13 mg
              Tamarix gallica        Whole plant   13 mg

Good agricultural and collection practice (GACP) was followed during the collection and manufacture of the herbal formulation (WHO 2003). Botanical identification and Ayurvedic criteria for desired quality were in accordance with the guidelines of Pharmacopoeial Standards of Ayurvedic formulations (1987) and were carried out by a qualified chemist approved by the Food and Drug Administration.

Geographical source and harvest time for each of the herbal ingredients was recorded. Caparis spinosa grows widely in stony soil of north western India and is transplanted during winter and spring. Cichorium intybus and Solanum nigrum grow on the plains of India up to 2100 metres in regions with a dry, temperate climate. Terminalia arjuna grows in most parts of India. Its bark is cut into pieces and dried in sunlight. Cassia occidentalis is a tropical annual herb found throughout India up to an altitude of 1200 metres. Tamarix gallica is found in sandy or gravelly areas of north India and grows in saline conditions.

This formulation has been approved by regulatory authorities in India as a herbal formulation.

Material and methods

Inclusion criteria

Patients suffering from liver disorders such as hepatitis, cirrhosis and non alcoholic hepatitis, diagnosed as per clinical and biochemical parameters were included in this study (Table 1).

Exclusion criteria

Patients with a history of allergic disorders and evidence of any malignancy, and pregnant and lactating women were excluded from the study (Table 1).

Study procedure

This study was carried out in 20 consecutive patients who attended the Gastroenterology Clinic at Malar Hospitals, Chennai, Tamil Nadu, India. The study protocol, case report forms (CRF), regulatory clearance documents, product related information and informed consent forms (in English and Tamil) were submitted to the institutional ethics committee and were approved by the same. The patients were informed about the study drug, its effects, duration of the trial and overall plan of the study and were included in the clinical study only after written informed consent was obtained from each of them. They were free to withdraw from the study if they so desired. The clinical history was noted by interviewing the patients. Thorough clinical examination, symptomatic evaluation was carried out and the details were noted in the CRF. Liver disease was determined clinically, the diagnosis of hepatitis B was confirmed by HBsAg serology, the diagnosis of alcoholic hepatitis was confirmed by ultrasonography. Patients were advised to take the herbal formulation in a dose of 1 capsule twice a day orally for 30 days.

The primary endpoints of the study were improvement in signs and symptoms of hepatic disorders such as anorexia, abdominal discomfort, flatulence, lethargy, nausea, hepatomegaly and jaundice, and improvement in the biochemical parameters, viz serum protein, serum bilirubin, serum glutamic oxaloacetic transaminase (SGOT) (replaced in Australia with aspartate aminotransferase--AST), serum glutamic pyruvic transaminase (SGPT) (replaced in Australia with alanine aminotransferase--ALT), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT). The secondary endpoints were adverse effects from the herbal formulation.

Adverse events

All adverse events either reported or observed by patients were recorded with information about severity, duration and action taken regarding the study drug. Relation of adverse events to the study medication was predefined as 'unrelated' (a reaction that does not follow a reasonable temporal sequence from the time of administration of the drug), 'possible' (follows a known response pattern to the suspected drug, but could have been produced by the patient's clinical state or other modes of therapy administered to the patient), and 'probable' (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the patient's clinical state).

For patients recorded as withdrawing from the study, efforts were made to ascertain the reason for the dropout. Non compliance (defined as failure to take less than 80% of the medication) was not regarded as treatment failure, and reasons for non compliance were recorded.

Statistical analysis

The results were expressed as the number of incidences for both clinical and physical signs and as mean [+ or -] SD for hematological and clinical evaluations. Statistical analyses were carried out using Fisher's exact test or paired student's t-test. The minimum level of significance was fixed at p<0.01.

Results

An open clinical trial was conducted with the Herbal Formulation capsules in 20 patients (16 males and 4 females) with a mean age of 42.9 [+ or -] 11.5 years. Six patients had hepatitis A infection, 2 patients were positive to HBsAg and remainder of the patients were suffering from alcohol related hepatic diseases. All patients received a daily dose of 1 capsule twice a day for a period of 30 days. They did not receive any other medication during the study period.

Clinical symptoms such as asthenia, easy fatigability, tiredness, nausea, anorexia, edema, abdominal discomfort, abdominal pain/tenderness, pruritus, fever, painful muscle cramps, and depression were evaluated for the presence or absence of symptoms before and after treatment.

At the beginning of the study, out of 20 patients, 18 had asthenia, 20 had fatigability, 17 had tiredness, 6 had nausea, 16 had anorexia, 15 had abdominal discomfort, 7 had abdominal pain/ tenderness, and 9 had jaundice (Table 2).

There was significant reduction in the above clinical symptoms by the end of the study period. By day 30, asthenia was present in only 3 patients, fatigability in 4, tiredness in 5, anorexia in 2, abdominal discomfort in 2, and jaundice in 3 patients. All patients had complete relief from nausea and abdominal pain or tenderness (Table 2).

Physical signs such as muscle wasting, loss of adipose tissue, jaundice, anemia, dehydration, cyanosis, spider nevi, excessive bruising, petechial hemorrhages, hyper-pigmentation, hepatomegaly, splenomegaly, peripheral edema, and ascites were evaluated.

Hemoglobin, red blood cell (RBC), white blood cell (WBC), erythrocyte sedimentation rate (ESR), packed cell volume (PCV) and platelet counts were performed for routine hematology. Biochemical observations included SGOT, SGPT, ALP, GGT, total protein, albumin, globulin, and bilirubin. There was significant renormalisation of the biochemical parameters of liver functions after 30 days of treatment with the herbal formulation. Significant reduction in the levels of SGOT (p<0.01), ALP (p<0.01), GGT (p<0.01), and sodium butyrate (SB) (p<0.01) were observed at the end of the study (Table 3). There was no clinically significant alteration in hematological and other biochemical safety parameters as compared to pretreatment values.

There were no clinically significant adverse effects, either observed or reported, following treatment with the herbal formulation during the entire study period, and the overall compliance to the drug treatment was found to be excellent. The overall impression by the investigator showed excellent improvement in 40%, good improvement in 50%, slight improvement in 5%, and no change in 5% of the cases. The overall impression by the patients showed excellent improvement in 40%, good improvement in 55%, and no change in 5% of the cases.

Discussion

Liver disorders are common clinical problems which need a safe and effective drug therapy. Alcoholic and non alcoholic hepatitis are frequent causes of hepatic dysfunction. Hepatitis A is a benign form of hepatitis. Hepatitis B can run in chronicity and can lead to cirrhosis of the liver (Krugman 1962). The traditional healer's approach to the management of chronic liver disease is to regulate and strengthen the liver, gastrointestinal and immune system (Goldberg 1969; Jafri 1999). The protection of liver cells against toxic materials including drugs, lipid peroxidation and free radical injury may decrease inflammation, improve liver blood flow and ultimately help in reduction of further liver damage (Jiang 1997).

In the present study, the efficacy of a herbal formulation on various liver disorders was investigated. It is evident from the results that there was a significant improvement in liver function tests including SGOT, SGPT, ALP, GGT and total bilirubin. A significant improvement was produced in various clinical parameters (Table 2) at the end of 28 days. None of the patients had any adverse effects due to administration of the formulation.

Although the exact mechanism of this herbal formulation on liver function and body metabolism is not yet clearly known, its ingredients have been shown to influence the cellular functions of body metabolism. The diuretic effect of Terminalia arjuna and anti-inflammatory and anti-immunotoxicity effect of Cichorium intybus have been shown in clinical and experimental studies (Kim 2002, Langmead 2001, Mathur 1994). The antioxidative and anti-hepatotoxicity effect of esculetin and P. methoxybenzoic acid, the main constituents of Cichorium intybus and Capparis spinosa respectively, have been reported in chemically induced hepatotoxicity in experimental animals (McPhail 2003, Mehrotra 1973, Munasinghe 2001). Achillea millefolium, another component of the herbal formulation, contains several bioactive constituents including flavonoids and terpenoids with antioxidative and anti-inflammatory properties (Patrick 1999, Pocock 1999, Saller 2001). The antioxidative property of Tamarix gallica and inhibitory effect of Solanum nigrum crude extract on free radical mediated DNA damage increase the hepatoprotective effect of the herbal formulation (Sultana 1995, Sumitra 2001). The antioxidative and anti-lipoproxidative effect, and increase in glutathione content of the liver cell have been observed with arjunolic acid and flavonoids present in Terminalia arjuna (Tubaro 1988, Vogel 1975).

Phytomedicines work on many physiological functions and produce synergy amongst constituents (Williamson 2001). The synergistic actions exhibited by all the ingredient herbs might be responsible for the hepatoprotective effect of this herbal formulation.

Conclusion

In this study it was found that the herbal formulation possesses significant hepatoprotective activity in various liver disorders and the formulation is safe without any serious adverse effect. A further study in a larger population in a randomised trial will be required to confirm the evidence seen in the present clinical study.

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Disclosure of conflicting interest Dr Pralhad S Patki and Dr SK Mitra are full time employees of The Himalaya Drug Company. S Ganesh is a Consultant Gastroenterologist and Hepatologist at Chennai and has no financial interest in The Himalaya Drug Company.

S Ganesh MD Dip Gastro RCP (London)

Consultant Gastroenterologist and Hepatologist, Malar Hospitals Ltd. Chennai, Tamil Nadu, India

Pralhad S Patki* MD

Head Medical Services and Clinical Trials

SK Mitra MD

Executive Director R & D Centre. The Himalaya Drug Company, Bangalore-562 123, India.

* Corresponding Author Phone [phone], Fax : [phone], email [e-mail]