Ethnopharmacological Approaches for Therapy of Jaundice: Part I

Jaundice: an overview

Jaundice is one of the most wide spread disease conditions occurring throughout the world. It is also a life-threatening condition, mostly in the underdeveloped countries. Jaundice is caused by elevated serum bilirubin concentration in the body (Ullah et al., 2016). The term “jaundice” is derived from the French word “jaune,” which literally means yellow (Constantin, 2011). The metabolism of bilirubin takes place through the hemolysis of red blood cells (RBCs), which leads to the release of hemoglobin. The heme oxygenase degrades heme into biliverdin and carbon monoxide within the reticuloendothelial system. Biliverdin is then converted to unconjugated bilirubin by biliverdin reductase (Figure 1). The unconjugated bilirubin binds to albumin and is transported to the liver. The unbound unconjugated bilirubin is toxic to the central nervous system as it can cross the blood-brain barrier (BBB) (Brites, 2012; Olds and Oghalai, 2015; Jasprova et al., 2016).

Jaundice is mainly observed in neonates and is not common in adults. However, when it is present in adults, it suggests a serious predicament. In developing countries in particular, jaundice is very prevalent and can be life-threatening. The pathophysiology of jaundice and the metabolism of bilirubin take place in three phases: viz. pre-hepatic phase, the intra-hepatic phase, and the post-hepatic phase. A problem in any of these phases can lead to jaundice. Bilirubin is the metabolic (or breakdown) product of hemoglobin in erythrocytes (Figure 2). The heme metabolism has a central role for bilirubin production (Memon et al., 2016). Heme is an iron-containing porphyrin that is present in hemoglobin, myoglobin, and numerous enzymes, such as hepatic cytochromes (de Visser and Stillman, 2016). It is estimated that 80% of bilirubin formation takes place through heme breakdown in reticuloendothelial cells, spleen, or liver.

The unconjugated bilirubin is largely insoluble in water, but can be reversibly conjugated to albumin. It is transported to the liver, escaping the filtration in kidneys. Generally 90–95% of the bilirubin circulating in the blood is unconjugated. In the case of hypoalbuminemia (a type of hypoproteinemia), bilirubin displacement from the albumin molecules may cause diffusion of bilirubin across the BBB. This is by means of an assortment of drugs and/or increase in the blood unconjugated bilirubin levels. If the higher amount of bilirubin crosses the BBB and the level of unconjugated bilirubin in the blood reaches 15–20 mg/dL, it causes bilirubin encephalopathy, or kernicterus (a bilirubin induced brain dysfunction; Kruger, 2011). The conjugation of bilirubin takes place across the sinusoidal membrane within the hepatocytes after the hepatic uptake, followed by the action of microsomal uridine diphosphoglucuronyl transferase (UDPGT), converting bilirubin to water-soluble form and facilitating its excretion into bile and by the urine (Kruger, 2011). The metabolism of heme results in about 4 mg/kg/day bilirubin production. Maximum amount (about 80%) of heme moiety is utilized by the catabolism of erythrocytes and the rest 20% resulting from the ineffective erythropoiesis and breakdown of muscle myoglobin and cytochromes (Pashankar and Schreiber, 2001).

The major manifestation of jaundice is the yellow color of skin and mucous membranes due to deposition/gathering of bile pigments in blood and body tissues by bilirubin. The color expression is the same in case of carotenemia, but in this condition the bilirubin levels are normal (Kruger, 2011; Schlosser et al., 2011). The pigment depositions are of little effect for most newborns, but in preterm infants even lower doses of bilirubin have the potential for causing kernicterus (Maisels, 2000; Santos et al., 2008). Adults usually have a normal range of serum total bilirubin concentration <1 mg/dL (Roy-Chowdhury and Roy-Chowdhury, 2011). There are several parameters by which the jaundice can be diagnosed once the bilirubin concentration reaches 2.0–2.5 mg/dL. However, even experienced clinicians may not observe the yellow skin coloration until the serum bilirubin levels reach 7–8 mg/dL. It is believed that this coloration is clinically detected once the serum bilirubin level increases above 3 mg/dL (51.3 μmol/L; Roche and Kobos, 2004).

The occurrence of jaundice (icterus neonatorum) in newborns is observed for centuries. Juncker and Stahl (1724), in the Conspectus Medicinae Theoretico praticae distinguished “true jaundice” and “the icteric tinge which may be observed in infants, immediately after birth” (Lauer and Spector, 2011). A subcommittee on hyperbilirubinaemia estimated that apparent jaundice developed approximately in 60% of full term babies along with 85% of pre-term babies and about 10% of breast fed babies are still jaundiced at age of 1 month (Dennery et al., 2001; Zeitoun et al., 2013). The neonatal jaundice is apparent on day 3, peaking on day 5–7 and resolving by day 14 is called “physiological jaundice,” and it is considered as normal physiological condition. The “physiological” jaundice is usually benign, however brain injury and lifelong disability can occur if serum bilirubin (unconjugated), which is neurotoxic, is too high level and crosses the BBB causing damage of auditory nerve and basal ganglia (Subcommittee on Hyperbilirubinemia American Academy of Pediatrics, 2004). Such condition is rare (about seven new cases each year in the United Kingdom; Manning et al., 2007) and sequel include deafness, choreoathetoid cerebral palsy, and upgaze palsy. The signs and symptoms of jaundice are associated with serious liver disease, such as biliary atresia, whose treatment should be done at the age of 6 weeks (Hartley et al., 2009; Lauer and Spector, 2011). It should be noted that the disease imposes large social costs (Ebrahimimd et al., 2011). Most commonly accepted treatment of hyperbilirubinemia is phototherapy. However, there are several complications like dehydration, retinal injury, bronze baby syndrome and diarrhea, which can put the baby at risk (Stoll and Kliegman, 2004; Kliegman et al., 2007; Ebrahimimd et al., 2011).

History of jaundice

The history of jaundice is very long and is described as a sign of “causeless hatred” in the Babylonian Talmud (Poduri, 2016). There are various ancient references related to jaundice which are presented in Babylonian Talmud, Sumerian Tablets, Ebers papyrus, and in Ancient Ayurveda (the Indian traditional system of medicine; Poduri, 2016).

Moreover, the work of Hippocrates (460–370 B.C.) also provided references to jaundice (Schmid, 2001; Bynum, 2008). The terms that are used in hepatology like “hepatic,” “liver,” and “jaundice” have been originated from Greek, Sanskrit and French languages, respectively (Riva et al., 2011; Definition, 2016)¹. The most primitive Latin word used to indicate the liver was “iecur,” which is likely from Sanskrit “yakrt” (Riva et al., 2011). The word “jaundice” derives from an old French word “jalnice,” followed by “jaunice,” which means “yellowness.” In earlier times before 1800, there was limited notion about jaundice. Its relation to the alcohol uptake was described in 1836 by Addison (Gao and Bataller, 2011). In 1885 Lühraman recorded the occurrence of jaundice as an adverse effect of vaccination (Thomas et al., 2013; Trepo, 2014). In 1908 McDonald suggested that the probable cause of jaundice might be an agent, which was much smaller than bacterium (McDonald, 1908; Thomas et al., 2015). This idea was developed in 1923 by the hypothesis that virus was the cause for jaundice (Thomas et al., 2013; Poduri, 2016). A great number of death cases were observed during World War II (WWII) by hepatitis (1939–1945). During WWII, it was estimated that around 16 million people were killed as a consequence of hepatitis (Trepo, 2014). Therefore, different liver disease conditions like autoimmune hepatitis, liver cirrhosis, hepatitis A, B, C, D, E, hepatic carcinoma, or hemolytic anemia may lead to jaundice (Wahab et al., 2004; Amiri et al., 2014).

Discovery of hepatitis viruses

Most common hepatitis viruses are categorized as hepatitis-A (HAV), hepatitis-B (HBV), hepatitis-C (HCV), hepatitis-D (HDV), and hepatitis-E (HEV). Although, HBV, HCV, and HDV are spread mainly by blood exposure, HBV is transmitted mostly by unprotected sex. On the other hand HAV and HEV are spread predominantly by fecal-oral means (Singhal et al., 2009; Puri, 2014). A brief account on the discovery of these hepatitis viruses are presented here:

Ethnopharmacological approaches for management of jaundice: history, significance, and diversity of the used medicinal plants

According to the review by Hatfield (2004), several unusual practices have been employed to treat jaundice. In the British traditional medicine, there are some unusual home remedies for jaundice. A grotesque fallacy from Staffordshire is via the use of a bladder, which is filled by the patient's urine and placed close to the fire. It is believed that the patient recovers as it dries out. Another example of this kind is recorded from west Sussex, where an alive spider is rolled up in its own web and gulp down as a pill to cure jaundice. In Westmoreland alive head lice, and roasted powdered earthworms in Ireland, are ingested to cure jaundice (Hatfield, 2004). The use of snails was also found during seventeenth century as a cure for jaundice. Use of sheep's dung in water, giving the patient a violent fright (Hatfield, 2004) and a decoction of the common slater (woodlouse) in beer is also found to cure jaundice in Scotland. Urine was also used in various countries viz. in Ireland, urine mingled with milk like a drink against jaundice. In Yorkshire, baked rye cake with patient's urine under slow burning was believed to fade the illness away (Hatfield, 2004). In India such type of unusual practices were very common in the past. Certain people claimed to cure jaundice by spiritual practices and the use of Mantras (a sacred utterance, a spiritual sound, mainly are group of words in Sanskrit) along with some precautions, such as avoiding the fried and oily food, avoiding yellow color food especially use of turmeric in food. The practitioners used oil along with Durva [Cynodon dactylon (L.) Pers.], and used a bronze coin to treat the patients, for 3–4 weeks and within this time the patient gets rid from jaundice.

Several household remedies are used for jaundice treatment including eggs, cider, tea made from oats (Avena sp.) and vinegar. Some less distasteful propositions were, to use pearls dissolved in vinegar (De Lys, 1948) and a mixture of horn scraping and honey (Allen, 1963). Eating shellfish is a suggestion of Japanese origin (UCLA Folk Archives, record number 23_5423). Similarly to the Yorkshire method, baking of cornmeal cake with the patient's urine and its burning was used to cure jaundice (Hyatt, 1965; Hatfield, 2004). Various amulets are also used in North American folk medicine against jaundice. Some of these were made up of metals such as a copper necklace, or coin worn around the neck (UCLA Folklore Archives, record number 11_6404; Hatfield, 2004); gold piece of $ 5 strapped to the chest, or red beets worn round the neck (Puckett, 1981). Dressing of the patient in yellow clothes is a common practice in Pennsylvania to cure jaundice, which is in fact a custom of Russian origin (Crosby, 1927; Hatfield, 2004). Transference is also a typical example of jaundice cure, in which hard-boiled eggs strung over a necklace or placed under the armpits overnight (Hyatt, 1965; Hatfield, 2004). The next morning the egg white would be yellow, and the patient becomes white (Rogers, 1941). Some other sundry remedies for children suffering from jaundice are to place baby between two pillows, which would “bleach” out the jaundice (UCLA Folklore Archives, record number 23_58900, Hatfield, 2004). Although, these are based on typical practices used in older times, presumably these “treatments” do not work.

In Ayurveda, a variety of pathological conditions associated with jaundice are described under the generalized title referred as “Pandu-roga” (generally considered as anemia) which is a Sanskrit term meaning yellowish pale, or white disease. One of the important unique texts of Ayurveda, the Charak Samhita, or Carak Samhita (Before second Century A.D.) described in detail the eight categories of Pandu-roga (wherein another term “Udarroga” is mentioned for gastroenterological disorder) including “Kamala,” which seems to be the most relevant for jaundice condition. It was further described that Kamala (jaundice) is not developed during the initial stage of the condition. The occurrence of jaundice may develop if the initial Pandu-roga is not cured properly, and if the patient consumes bile-producing food. There are several important symptoms attributed to Kamala, which seem to be clearly associated with jaundice. They include: yellowish to greenish-yellow coloration of urine, sclera, nails and skin, reduction in the power of the senses, weakness, anorexia, indigestion, burning sensation and sometimes red urine (Durkin, 1988). Charaka (Caraka) described the treatment of various Pandu-roga including Kamala by different methods like emesis, evacuation of bowels, ingestion of medicated ghee, diet rich in rice, wheat, barley, and broth of Mung leaves (Vigna radiata L. R. Wilczek), as well as the use of different medications, which could restore humoral balance. All categories of Pandu-roga were mainly described as caused by the eating habits, and that the excess of hot, sour, salty, lentils, sesame oil, and seed pulp may cause various gastrointestinal problems. As the Ayurveda also tells about the life style, it was further depicted that overindulgence in sexual intercourse, suppression and negligence of bodily urges, emotional attributes (anger, sorrow, worry etc.) and day time sleeping may also cause an imbalance among the three humors (Vata, Pitta, Kapha, which are the basis of Ayurveda) by provoking bile in excess amount. Such types of imbalance showed different symptoms of jaundice and mainly the yellow pigmentation of skin. Some of the frequently used plants described include Phyllanthus emblica L., Operculina turpethum (L.) Silva Manso, Azadirachta indica A. Juss., Zingiber officinale Roscoe, Piper longum L., P. nigrum L., Curcuma spp. Swertia chirayita (Roxb.) Buch.-Ham. ex C.B.Clarke, Picrorhiza kurroa Royle ex Benth., Terminalia bellirica (Gaertn.) Roxb., and T. chebula. Most of these plants are already listed in Table 1, which indicates the significance of the Ayurvedic plants for the treatment of this condition. In Nepal it was described that some of the Vaidyas are being practicing Ayurved (Indian System of medicine). The Vaidyas of Kathmandu used to treat several ailments, although they are renowned for their ability to treat jaundice. Jaundice is considered as one of the most common disease conditions in Nepal and its association with viral hepatitis. An interesting fact reported by Durkin in 1988 is that, even though the people who generally do not rely on Ayurvedic treatment are also consulting to Vaidya, if jaundice occurs to them or their family members. It is also believed that effective treatment for jaundice is present in Ayurveda. The use of numerous plants in jaundice supports the above statement as Ayurveda utilizes a large number of medicinal plants and the major portion of Ayurvedic treatment relies on medicinal plant based formulations. The term Kamala and Kamala pitta are generally used by Vaidya in Nepal for jaundice. The cause of jaundice may include bile promoting food, dirty water intake from which the microbes could transmit and seasonal fluctuations (it was also observed that occurrence of jaundice is more frequent in autumn; Durkin, 1988).

Various herbal medicines for treatment of jaundice are being used from ancient times. Combination of Bogbean (Menyanthes trifoliate L.), raspberry (Rubus sp.) and wild mint (Mentha spp.) was used to treat jaundice (Beith, 1995; Hatfield, 2004). In Shetland, Bogbean is known as gulsa girse, which literally means “yellow sickness plant” (Vickery, 1995). The bark decoction of another important plant, Barberry (Berberis vulgaris L.) also known as the “jaundice tree” in Cornwall; has been widely used for the treatment of jaundice in England and Ireland (Vickery, 1995). Some other important plants used for jaundice treatment are: dandelion (Taraxacum campylodes G.E. Haglund), Ulex europaeus L. (Vickery, 1995; Hatfield, 2004), and nettle roots (probably Urtica dioca; Hatfield, 2004). Greater celandine (Chelidonium majus L.) is used for the treatment of infantile jaundice. Other plants used mainly in European countries for the treatment of jaundice are Primarose (Primula vulgaris Huds.) in Ireland, cowslip (Primula veris L.), in England, leaves of the savage tree (Juniperus sp.) in Wales, (EFS record number 221), chickweed (Tragopogon porrifolius L.), salsify [Stellaria media (L.) Vill.] in East England, Ulmus spp. boiled in milk in Herefordshire and Ireland (Vickery, 1995; Hatfield, 2004).

In Britain other herbal remedies are used like dandelion (Taraxacum sp.), greater celandine, which is either worn in the shoes (Lick and Brendle, 1923) or ingested (Meyer, 1985). Various botanical remedies like walnut bark (Juglans sp.), boneset (Eupatorium perfoliatum L.), hops (Humulus lupulus L.), wild cherry bark (Prunus serotina Ehrh.), black alder [Ilex verticillata (L.) A. Gray], leaves or bark of peach [Prunus persica (L.) Batsch], cinquefoil (Potentilla Canadensis L.) (Meyer, 1985), strawberry leaves (Fragaria spp.) (Lick and Brendle, 1923), a tea made from catnip (Nepeta cataria L.) (Puckett, 1981) or from mullein (Verbascum sp.) (Parler, 1962) are used to treat jaundice. Some other important herbal infusion which are used to treat jaundice are yarrow (Achillea millefolium L.) (Hendricks, 1959), crossvine (Bignonia capreolata L.) (Rogers, 1941), calamus root (Acorus calamus L.) (Puckett, 1981), mayapple root (Podophyllum peltatum L.) (Clark, 1970), yellow dock root (Rumex crispus L.) (Lick and Brendle, 1923), rosemary leaves (Rosmarinus officinalis L.) (UCLA Folklore Archives, record number 4_2092), ironwood bark (Carpinus caroliniana Walter), and St. John's wort (Hypericum perforatum L.) (Hatfield, 2004). In Carolina, tea brewed from wild oranges and basil (Ocimum basilicum L.) (Brown, 1952-1964) was used for treating jaundice. In the Midwest, bruised lobelia and red pepper pods in whisky were used (Pickard and Buley, 1945). In Indiana a mixture containing bitter root (Lewisia sp.), red sumac (Rhus sp.), wild cherry bark (Prunus sp.), sarsaparilla root, and wild poplar root (Populus sp.) was used (Halpert, 1950; Hatfield, 2004). Haematoxylon spp. (longwood) has been used to treat jaundice in Mexico. The Haematoxylon spp. extract is utilized by two ways drinking the liquid extract, or by placing the glassful of extract on the window still for patient to gawk; further it was hoped to transfer the yellow color from the patient to the liquid (Curtin, 1907; Hatfield, 2004). Vegetables viz. collards (Brassica oleracea L.) (Browne, 1958), artichokes (Helianthus tuberosus L.) were also found useful in jaundice treatment, (UCLA Folklore Achieves, record number 6_7607). The use of tobacco (Nicotiana spp.) alleviate jaundice (Smith, 1929) and daisies (Bellis perennis L.) is recommended for the re-coloration after jaundice treatment (Clark, 1970). Native American practices are also rich in terms of plants for hepatic disorder. For example the use of Juglans cinerea L. is recommended from Iroquois (Herrick, 1977; Hatfield, 2004).

There is an emerging interest in the use of medicinal plants that have been used traditionally for treating various diseases. This is because medicinal plants have the lesser adverse effects and fewer complications compared to synthetic drugs. This is an important advantage of plant derived drugs, which is also advised by the World Health Organization (WHO). The search of bilirubin reducing substances of herbal origin has gained particular interest in recent times (Dennery, 2002; Wong et al., 2005). A number of plant derived products are used either alone, or in combination with various other modern treatment such as exchange transfusion or the phototherapy of infants with high bilirubin concentration (Ebrahimimd et al., 2011). Systematic scientific studies are required to evaluate the safety, efficacy and toxicity profile of various herbal drugs (Kunwar et al., 2009). The utilization of the medicinal plants in the treatment of jaundice is also evident from the number of case series, which exhibited faster reduction of jaundice than western medicine treatment (Ebrahimimd et al., 2011).

The induction of glutathione S-transferase and UDP-glucouronyl transferase (UGT) and the effect on bilirubin metabolism in rats was reported upon treatment with Scutellaria, Rheum officinale L., Artemesia, and Gardenia. The combination of extracts from the above mentioned plants is known as “Yin Zhi Huang” in the Chinese traditional medicine and is used in Asia for the management and treatment of neonatal jaundice via enhancement of bilirubin clearance (Yang and Lu, 1984; Chen and Guan, 1985; Dong et al., 1992; Elferink, 2004). Various medicinal plants have also been used from an ancient time in different countries, including Iran, China, Ethiopia, Mexico, West Africa, Turkey, Peru, Nepal etc., but there are still more studies required to prove their efficacy. Clinical studies have also been carried out in Iran to evaluate the effect of aqueous extract of Zizyphus jujuba Mill. on the neonatal jaundice. The results showed a straight effect of the plant extract on the neonates. The use of medicinal plants in the treatment of jaundice showed in some studies more potent stimulatory effect on bilirubin clearance when compared to phenobarbital (Yin et al., 1993; Zhao et al., 2006). Some of the plants such as Z. jujuba are used in the reinforcement of liver function during jaundice (Chan, 1994; Huang, 1998; Ebrahimimd et al., 2011). However there are some limitations present in the study carried out with Z. jujuba as it was shown effective in the treatment against neonatal jaundice during the first 12 h, but it was not found effective in the consecutive days (Ebrahimimd et al., 2011). The use of herbal medicines to heal the jaundice was also reported from Mashhad city in Iran, where the disease was found to be major health problem (Amiri et al., 2014).

There are two widely accepted methods of neonatal jaundice treatment, phototherapy and blood exchange (Amiri et al., 2014; Chen et al., 2017). In addition, herbal remedies are also very popular in the treatment of jaundice, especially in the Iranian tradition (Rajaei and Mohamadi, 2012; Amiri et al., 2014). A number of plant species have been utilized in Iran (Table 1 and Figure 3). There are very limited pharmacological interventions, which are used for the treatment of neonatal jaundice. The available pharmacological approaches for treatment of neonatal jaundice are based on different mechanisms of action. Metalloporphyrins, for example act via inhibition of heme oxygenase—the rate limiting enzyme in bilirubin production. The metalloporphyrin consists of a biocompatible metal ion, which does not degrade in tissues and is not photochemically active. Some of the important tissue heme oxygenase inhibitors are chromium mesoporphyrin (CrMP) and tin mesoporphyrin (SnMP) (Vreman et al., 1993; Dennery, 2002). Although, the metalloporphyrin are used frequently and are highly effective, some of those compounds are photochemically active (Dennery, 2002; Lee et al., 2017). Some of the studies revealed a dosage dependent mortality associated with SnMP application in neonatal Wistar rats (Hintz et al., 1990), moreover lipid peroxidation and heamolysis of RBCs was also reported (Keino et al., 1990). Some other adverse effect such as arrhythmia, tachyphylaxis (which is due to the induction of HO-1 protein and mRNA) etc. were also reported upon metalloporphyrins use. Though CrMP does not possess phototoxicity, it cannot be considered as safe because of the carcinogenic effect of Cr metal (De Flora et al., 1980; Voitkun et al., 1998; Dillon et al., 2000). Another important therapeutic regimen for neonatal jaundice is D-Penicillamine. The drug is used to cure neonatal jaundice mainly in Europe but not in the USA (Dennery, 2002). Its main mechanism of action is by the inhibition of HO activity (Juckett et al., 1998). Still there are risks of fatalities associated with this drug, along with the onset of aplastic anemia, thrombocytopenia, myasthenia gravis and Goodpasture syndrome (Louie et al., 1986; Peces et al., 1987; Fishel et al., 1989; Kaufman et al., 1996; Narayanan and Behari, 1999; Teive et al., 2017).

An extensive review has been carried out to explore the use of medicinal plants for jaundice treatment. A total of 207 plant species have been documented and presented in Table 1. The botanical name of the plant, family with the country name from where the plant is reported followed by formulation used for jaundice are summarized and web hits from Google scholar were gathered through Boolean information retrieval method using plant name with “AND” operator (Pohl et al., 2010).

Our work is the first review, which presents comprehensive documentation of the ethnomedicinal uses of the plants for the prevention and treatment of jaundice. Large number of medicinal plants has been shown to have potential in the development of approaches to obtain therapeutic regimen for the treatment of jaundice, although some of the molecules like sylimarin and andrographolide are already well established and widely used for the management of hepatic disorders worldwide. Many medicinal plants are being used from a long back in several countries. Graphical representation at Figure 3 shows the number of medicinal plants used for jaundice in 20 different countries/region, which have been documented in the review.

Conclusion

Various new chemical entities have been developed from natural products, which have been filed in last few decades. Ethnopharmacological information is of prime importance for discovery and usage of significant therapeutically important molecules either obtained from natural sources, or inspired by nature. In this first part of our review, we discussed the history, metabolism process; some unusual practices used in older times and a comprehensive detail about 207 plants, which are used in the treatment or management of jaundice. The substantiation presented is an indicative of the utilization of the plants in the prevention and/or treatment of jaundice. Though there is tremendous ethnopharmacological information about the plants involved in jaundice treatment, only some of them were used in clinical trials and have been explored for their mechanism of action. These studies will be covered in the next part of the review.

Author contributions

DT, AM, EP, ZM, YL, and AA have written the first draft of the manuscript. AS, SN, LH, and JH revised and improved the first draft. All authors have seen and agreed on the finally submitted version of the manuscript.