Medicinal Plants and Their Finished Marketed Herbal Products Used for Treatment of Liver Diseases in Ghana; A Field Survey and Review

Background and Objective: Hepatic disorders are conditions that affect the structure or function of the human liver. Causes include microbes and their toxins, ionizing radiations and abuse of drugs. Medicinal plant products have been an alternative for the management of these diseases due to the expensive, unavailability and harmful side effects of pharmaceutical drugs. The aim of this study was to determine whether plant species used in preparing herbal medicinal products for treatment of liver diseases have reported hepatoprotective activity. Materials and Methods: A field survey was conducted using information from television, radio and market vans to identify the medicines and purchase them from the herbal shops. The plant species and parts used in manufacturing were extracted from the product insert and the Traditional and Alternative Medicine Council logbook. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) instrument was adopted in conducting the review. A search was conducted on Google Scholar, PubMed and Elsevier databases on hepatoprotection activity of the plant species. Results: In all, 175 articles met the criteria for the quantitative synthesis and were used for the review. For the plants, 56 species were used by 20 manufacturing companies in producing 25 herbal medicinal products. Khaya senegalensis was the most predominant plant species (9/25, 36.0% products). In terms of parts, leaves (40/56,71.4% of plant species) were the most prevalent part used. On databases, 41/56 (73.2%) plant species had hepatoprotective activity while 15 (26.8%) had no data for hepatoprotective activity. Crataegus oxyacantha was the plant species with the most parts reported parts (7 different parts). Moringa oleifera was most extracted (7 different solvents) and most tested against hepatotoxicity induced with 20 different toxicants. Conclusion: There is sufficient scientific data on the hepatotoxicity activity of plant species used for herbal formulations against liver disorders. Practitioners and Researchers should focus on isolation and testing of the active phytochemicals.


INTRODUCTION
The liver performs various physiological functions that ensure systemic homeostasis for optimum metabolic activities, growth and repairs 1,2 .The liver is also involved in biosynthesis of amino acids, bile and clotting factors 3 .Detoxification of drugs, xenobiotics, heavy metals, food toxins, toxins from pesticides, plastics, weedicides and food additives 4 are also undertaken by the liver.The liver is further responsible for the storage of glycogen and fat-soluble vitamins 5 .
Hepatic disorders are conditions that alter the structure or functions of the liver resulting in alteration in its physiological activities 6,7 .They include hepatitis, cirrhosis, hepatocellular carcinoma, hepatoma, hepatosteatosis, jaundice, cholestatic injury, hepatobiliary obstruction, hepatovascular lesions and hepatozonal necrosis 8,9 .Hepatic diseases are caused by pathogens, toxins and environmental contaminants such as pesticides, weedicides, plastics, heavy metals and factory waste 10,11 .Abuse of alcohol, pharmaceutical drugs and food additives as well as iron overload also cause hepatic disorders [12][13][14] .
Globally, 10% of the world population is living with various complications of hepatic disorders, leading to a million deaths yearly 15 .In Sub-Saharan Africa, 250 million persons are affected by various hepatic disorders whereas in Ghana, complications of hepatitis B and C alone account for 10,000 deaths yearly 16,17 .
Serum markers of liver function and histopathological examination have been used to diagnose and characterize hepatic disorders 18 .Elevation in serum transaminases and bilirubin with low levels of proteins indicates parenchymal hepatic disease and hepatosteatosis 19 .Hepatobilliary and cholestatic conditions are characterized by high serum alkaline phosphatase (ALP) and gamma gutammyl transferase (GGT) [20][21][22] .
Histopathological indications of nuclear pkynosis, cytoplasmic pigmentation and DNA fragmentation are features of hepatic necrosis 23 .
Pathophysiology of liver diseases is centered on oxidative stress and synthesis of abnormal physiological proteins 23 .Oxidative stress results from overproduction of reactive oxygen, nitrogen and sulphate species from heavy metals, aflatoxin B1 and alcohol 24,25 .Consequently, these reactive species deplete glutathione stores and inhibit synthesis of free radicals scavenging enzymes such as catalase, glutathione peroxidase and superoxide dismutase 26,27 .Oxidative stress also activates the transcription factor nuclear factor-kappa beta (NF-kβ) 28 .Activated nuclear factor-kappa beta (NF-kβ) translocates from cytosol to nucleus where it causes continuous overexpression of proinflammatory and fibrogenic cytokines including tumor nuclear factor alpha (TNF-α), interleukin-6 (IL-6), transforming growth factor-beta (TGF-β) and epidermal growth factor (EGF) 29,30 .These pro-inflammatory cytokines result in sustained differentiation and proliferation of hepatic stellate cells into myoblast cells with collagen and muscle actins resulting in cirrhosis of the liver 31,32 .Cirrhosis obstructs blood flow to the liver resulting in hepatocyte hypoxia and necrosis 33 .In oxidative stress, transcription factors, sterol regulatory element binding protein-1c (SREPBP-1c), peroxisome proliferator-activated receptor-alpha (PPAR-α) and carnitine palmitoyl transferase-1 (CPT-1) are also overexpressed leading to hepatic lipogenesis, peroxidation and steatosis 34,35 .Pharmaceutical drugs have been the primary line of treatment for hepatic conditions in Ghana 36 .However, due to unavailability, cost and deleterious side effects, herbal medicines prepared from parts of medicinal plants have been used as alternatives 37,38 .The majority of plant-based Herbal Medical Practitioners (HMPs) in Ghana rely on folk knowledge and common daily experiences to select the choice of plant species and parts for preparation of medicines to treat hepatic diseases [39][40][41] .This study aimed to determine whether plant species used in preparing herbal medicinal products for the treatment of liver diseases have reported hepatoprotective activity.Diseases that herbal products were targeted in addition to liver diseases: Apart from liver-related diseases, herbal drugs were made for other sicknesses as presented in Fig. 1.Fever was the most frequent targeted by 8 (32%) products followed by joint pain 6 (24%) products.Malaria, typhoid and hypertension were each targeted by 3 (12%) products.About 2 (8%) products are made against immune disorders, ulcers and piles while 1(4%) product was made against kidney diseases.Types of extraction solvents used to extract plant parts: Various solvents including distilled water, ethanol, methanol, phenol, chloroform, petroleum ether and butanol were used to extract plant active components and indicated in Table 4.

Parts of the plants
Toxins used to induce liver diseases and tested against plant extracts: Various substances including carbon tetrachloride, paracetamol, tuberculosis drugs, etc. were used to induce liver disease in experimental models and then challenged with plant extracts.------------------------------------------------------------------------------- Comparison between frequency of plant usage and reported data on scientific reports: A comparison was made to determine if frequency of data on hepatoprotective activity of a plant species in terms of parts, extracting solvents and testing models determine its usage to formulate a herbal product and vice versa.There was no significant difference between the frequency of usage in a herbal product and that of a number of parts as well as a number of extraction solvents reported.There was however significant difference between frequency usage in a product and number of toxins used in inducing models (p = 0.017).

DISCUSSION
Majority of the plant species (41/56, 73.2%) used in formulating the herbal products had data on the search engines in terms of parts, extracting solvents and inducing models.Whereas the products and the companies were wholly from Ghana, most of the journals reviewed were not published by Ghanaian Authors.This suggests that most of the plant species in Ghana have active components that can restore liver injury or companies and practitioners are relying on scientific information on the choice of plants for their medicines.This can also be attributed to the rapid upgrading of herbal medical practice in industry, academia and research.However, the level of herbal medicinal plants used for liver diseases is lower reported number of medicinal plants used for liver diseases in China, Korea and India 42 .van Quan et al. 41 reported that all the 300 plants used for liver treatment in Chinese traditional medicines have been test for hepatoxicity including hepatoxins.Jităreanu et al. 42 also reported that over 90% of 3000 medicinal plant species of Ancient Greek and Korea origins have been test for liver nutrients and toxins.Luo et al. 43 also reported that heavy metals and phytochemical screening has been achieved for all Taiwan medicinal plants.China, Korea and Taiwan have reported data on medicinal plants than Ghana due to the reliance on ancestral knowledge, superstition and lack of funding for scientific research in Ghana 44 .
A greater number of the herbal products (17/25, 68.0%) were in the liquid form.Liquid phase of a product provides appropriate surface areas which increase the rate of absorption into the blood when ingested or injected.It also provides a large surface area for reaction with enzyme and other components for effective pharmacokinetics.Formulation of liquid of medicinal is also more cost-effective industrial process because it requires less effort, personnel and processes.Rubio et al. 45 also found leaves to be the predominant part of the medicinal plants used for herbal products.
Khaya senegalensis (Mahogany) was the most predominant plant used in formulating the herbal products.Khaya senegalensis is abundant in all parts of Ghana where it used as banks on roads, folder for ruminants and for building purposes.Herbal Medical Practice apart from health benefits, it's also an economic and industrial activity that depend heavily on the availability of raw plant materials.Khaya senegalensis has also been long used in Ghanaian ancient medicine to treat illness including jaundice.The abundance of Khaya senegalensis and its long use in folk medicine could account for its frequent use in the formulation of these products.Recent works by Ssenku et al. 46 found Khaya senegalensis as the most common plant species used for herbal medicinal products.
Leaves were also the most prevalent plant part used in the manufacturing of these herbal products.This could to attributed to the fact that leaves accumulate more synthetic plant nutrients, accumulate fewer plant toxins and are more conspicuous 46 .While the roots of the plants hold the plant firmly to the ground and absorb water, minerals and chemicals from the underground.The roots are likely to accumulate minerals, heavy metals and other chemicals from fertilizers.The leaves are responsible for excretion, photosynthesis and respiration and could accumulate metabolites and excretory products 46,47  Finally, there was a significance of difference between the frequency of usage in a herbal product and number of toxins used to induce a model for study.Scientific investigation of hepato-efficacy of a plant extract involves modelling the liver diseases in an organism or tissue and challenged with the plant extract.
Whereas few parts of plants and solvents exist, there are over 65 substances that can be used to induce liver disease.Further, the nature of the toxin determines the kind of liver disease either acute, chronic, glandular, steatosis, parenchymal, hepato-biliary, or zonal that will be modelled.These toxins therefore influence the scientific investigation and reports which in turn influence the choice of the plant or part a practitioner or manufacturer chooses.

CONCLUSION
Majority of the herbal medicinal plants in Ghana have been tested against induced liver diseases and reported in the major scientific databases.Khaya senegalensis is the predominant plant used to manufacturing herbal medicinal products for treatment of liver diseases in Ghana.Further phytochemical screening, toxicity and testing in animal models are required to determine the safety and efficacy of the remaining plants without reported data in databases.

SIGNIFICANCE STATEMENT
The study provided data on the number and parts of herbal medicinal plants used for treatment of liver diseases in Ghana with and without reported hepatotoxicity in the major scientific databases.The study reveals majority of Ghana medicinal plants have been demonstrated against induced hepatotoxicity in various models.This forms basis for selection of candidate plant raw materials and further phytochemical and mechanisms studies.

16 Number
used to formulate the herbal products: Different parts of the same or different plant species were used in manufacturing a particular product.From Fig. 2, the majority of the plant species https://doi.org/10.3923/rjmp.2024.13.23 | Page r t e n s i o n D i a b e t e s T y h o i d M a l a r i a J o i n t p a i n F e v e r P l a n t p a r t R o o t s B

Table 1 :
Articles used for the review of plant species

Categorization of the plant species, parts and diseases according to information from literature databases
: On databases, 41/56 (73.2%) plant species had hepatoprotective activity while 15 (26.8%) had no data for hepatoprotective activity as indicated in Table2.

Frequency of parts of the plant species reported:
From data search, several parts of 41 plant species including leaves, bark, wood, root, seed, bud, flowers, fruits, fig, sap, twist were extracted with various organic and inorganic solvents and test against hepatotoxicity induced by various toxins.Table3, indicates the number of parts of each plant species that was reported in scientific papers.

Table 5
, indicates the number of different toxins that were used to induce liver disease in an experimental models and test against each plant.https://doi.org/10.3923/rjmp.2024.13.23 | Page 17

Table 6 :
Comparison between frequency of plant species in herbal products and hepatoprotective activity in databasesNumber in reported scientifc data 49ringa oleifera is one of the plants that has been used in ancient medicines to treat several illnesses.It is also used in various purposes such as ornamentals, drinks, oils, vegetables, salat, etc. da Silva et al.48found Melissa officinalis (31.0%),Peumus boldus (24.4%),Mentha spicata (20.9%),Matricaria recutita L. (18.2%),Rosmarinus officinalis (17.0%) and Foeniculum vulgare (14.7%) were the most used in a pool of 79 medicinal plants in Brazil.Mintah et al.49found Azadirachta indica, Carica papaya, Mangifera indica, Moringa oleifera, Elaeis guineensis and Hibiscus sabdariffa as the most common medicinal plant species used for herbal medicines for liver diseases in Southern Ghana.
On the databases, Crataegus oxyacantha was most reported in terms of parts while Moringa oleifera was the most reported in terms of extracting solvents and inducing models.Crategus oxycanthea is comparatively more abundant and exists in more different and diverse parts than Moringa oleifera https://doi.org/10.3923/rjmp.2024.13.23 | Page 19 and others.