Gallstone Formation, Diagnosis, Treatment and Prevention

By Ram Prasad

Gallstone Formation, Diagnosis, Treatment, and Prevention describes the current scenario of gallstones and adopted treatment methods. It is a complete reference for researchers introducing new techniques to help prevent extreme treatments such as a cholecystectomy. This reference provides current knowledge and basic challenges of understanding gallstone formation, with all variations of composition including complications of the treatment process. This content directs researchers to focus on gallstone mechanisms to design and develop new treatment methods. The book provides all possible factors for gallstone formation as well as preventative measures.

• Offers treatment methods, including both chemical and herbal methods
• Presents mechanisms behind gallstone formation that are important to researchers to determine treatment methods that can prevent cholecystectomy
• Includes the latest research on acute pancreatitis, one of the major concerns of gastrointestinal disease
• Discusses the effects of gallstone as a cancer-causing mechanism

• Language: English
• Publisher: Academic Press
• Release date: Mar 11, 2024
• ISBN: 9780443160998

Book preview

Preface

Rajani Sharma, Shubha Rani Sharma and Ram Prasad

Gallstone, a major gastrointestinal disease has proved to be an economic, physical, and mental burden for patients. Gallstone disease is not very new but has been found to be prevalent since the BCE era. The presence of gallstones in Egyptian mummies supports this fact. The book aims to present all the existing facts about gallstones in a nutshell which would be helpful for the researcher and pharmacist to treat gallstones without involving cholecystectomy. The book begins with the historical perspective of gallstones in Chapter 1. This chapter deals with the prevalence and basic information that has persisted in the past medical information. Chapter 2 accounts for comparing gallstones with other types of stones: urinary and kidney stones. This chapter highlights the mechanisms of formation and distinction between gallstones and urinary stones. It strives to meticulously inspect the degree of variability and alignment between different types of stone diseases and discusses the approach of finding a novel treatment for its permanent cure.

As per the current knowledge, cholecystectomy is the most preferred treatment method for gallstones. In this method, the gallbladder is removed along with the gallstone. Although the patient can lead a normal life even without a gallbladder, they may have issues with fat digestion. Gallbladder role is not limited to the absorption of fat from the intestine rather the removal of the gallbladder witnesses several pathological conditions such as increased alanine aminotransferase or Gamma Glutamyl Transferase level, dyslipidemia, hypertension, insulin resistance, and even cirrhosis. Besides, lipid absorption bile acid plays a crucial role in controlling the systemic endocrine functions. The detergent nature of bile acids makes them strike cell membranes, followed by the secretion of cytokines and chemokines, which have a central role in the regulation of immunity and inflammation. Also, the detergent effect of bile acid has antimicrobial properties. Moreover, the gallbladder secretes specific proteins that maintain intestinal homeostasis by regulating the microbiota inside the gut. Chapter 3 provides information about the physiological function of the gallbladder, bile acid secretion, its functional regulation, role of gallbladder in immunity and metabolism, and some pathological conditions associated with metabolic disorders. This signifies the need to adopt a method that can prevent cholecystectomy. Hence, the next chapter deals with the factors prevailing for gallstone formation. Various factors can initiate the formation of gallstones such as age, gender, female physiological status, obesity, cardiovascular disease, microbiome, sugar metabolism, and various environmental exposures. These prevalent factors are discussed in this chapter. As per the evidence, all the stated factors do not have a direct connection with the gallbladder. These factors affect the liver which in fact affects the metabolism of bile and cholesterol. This ultimately affects the bile composition leading to the formation of gallstone. Chapter 5 discusses the events and mechanisms in the liver which regulate the occurrence of gallstones. It has been observed that people with severe liver diseases are at the highest surgical risk, so gallstone complications should be treated using noninvasive or minimally invasive procedures until the patient’s condition stabilizes. The most recent data on gallstone types, risk factors, and treatments are presented in this book chapter. The formation of gallstones is controlled by the metabolism of cholesterol and bile which takes place in liver and has genetic relationships. This shows that certain molecular mechanisms contribute to the formation of gallstones. Chapter 6 deals with the molecular pathways regulating the formation of gallstones. Various studies have demonstrated the presence of lith genes which are involved in disturbance in bile composition in the gallbladder, forming gallstones. Along with the genes, nuclear receptors also play a regulatory mechanism in stabilizing the bile composition. Apart from all these factors, the relationship between the microflora of the oral cavity and gastrointestinal tract has also been established. The fact is that the bile has an antimicrobial role, but the existence of microbes in gallbladder, which has similarities with the oral cavity, seems to be playing a role in the nucleation of gallstones. To find the evidence and clarification, Chapter 7 is formulated. Many studies support the role of the oral microbiome in controlling the motility of the gallbladder through immunomodulation hence directly participating in the pathogenesis of gallstones. The microbiome of the oral cavity has also been proven to be an efficient biomarker for gallstones. The current chapter highlights the importance of the microflora of the oral cavity in the diagnosis and primary prevention of gallstones.

Apart from the oral cavity, several bacteria in the biliary tract also contribute to the formation of gallstones. Such bacteria have beta-glucuronidase and urease-producing activity. Some intestinal bacteria produce DNA-damaging toxins, which increase the appearance of gallstones and cause chronic inflammation and reactive oxygen species–mediated genotoxicity. Hence, the role of microflora should also be considered for the treatment of gallstones. Chapter 8 briefs about the complete role of microflora which would direct to take measures for the development of drugs which would target the chemical composition and check the microbial growth.

Gallstone is also a factor for the induction of other diseases like acute pancreatitis. Furthermore, the existence of gallstones for longer periods of time in the gallbladder may prove to be a risk for the development of cancer in the gallbladder. The next section of the book deals with these two adverse effects. The major cause for the development of gallbladder cancer is the persistence of gallstones without showing any symptoms. There are various tests and techniques used to detect gallstones such as blood tests, abdominal ultrasound, endoscopic ultrasound, and other imaging tests. Chapter 11 deals with these diagnostic techniques and symptoms for early detection of gallstones. This would prevent further complications.

The last section of the book deals with the treatment of gallstones including natural as well as chemical methods. Probiotics efficiently alter the composition of gut microbiota and bile acid synthesis, leading to health benefits such as lowering cholesterol, which is subsequently helpful in ameliorating hypercholesterolemia. With the multiple benefits of probiotics, Chapter 12 aims to discuss the association of alterations in gut and biliary microbiota with GS formation and the influence of probiotics in the prevention and treatment of gallstone disease. Chapter 13 highlights the importance of herbal treatments in completely curing gallstones without any side effects. It focuses on the underlying mechanisms of herbal treatments in dealing with the change in the composition of bile and its potential effects on other organs of the human body.

The last two chapters of the book focus on the current challenges. However, in major cases, gallstone is not responsible for mortality but paves the way for the causation of cancer of the gallbladder. The relationship between the two is yet to be established completely. Chapter 14 throws light on critical intricacies in gallstone genesis and its correlation with gallbladder cancer. Chapter 15 is miscellaneous to the book as it has presented a case study based on in silico approach for gallstone treatment. In summary, this book provides complete information regarding gallstone based on evidences and recent research in a precise manner.

Introduction

The gallbladder, even though not considered a vital organ, plays a major role in the metabolism of fat, serving as a route for the elimination of cholesterol. The gallbladder stores the bile which is produced in the liver. Bile, as well as cholesterol, is formed in the liver and the extra cholesterol is either transported to gallbladder for the elimination or converted to bile acid. Bile is stored in the gallbladder till it is instructed to be secreted into the small intestine. Bile is composed of bile salts, bile pigments, mucus, phospholipids, and cholesterol, and the major position is composed of water. In normal circumstances, the cholesterol remains dissolved in the form of micelles in the bile while on excessive secretion of cholesterol or decreased concentration of bile salts and bile acids cholesterol precipitates. The precipitates act as nidus upon which additional deposition takes place and increases the size to a solid mass forming gallstones and the process is known as cholelithiasis. Gallstone admits a major factor for admission in hospitals and contributes to the economic burden. There are various factors influencing the formation of gallstones. It has been categorized under metabolic disease. Along with metabolism, gallbladder motility, bile composition, and regulation of nuclear receptors are considered major determining factors in gallstone formation. Various studies support the prevalence rate with gender and epidemiological factors. The epidemiology and dietary factors also affect the chemical composition of gallstone, because differences in the composition of gallstone complicate the process of chemical treatment.

Gallstones remain undetected until they block the bile duct. The blockage developed symptoms such as nausea, vomiting, right hypochondrium pain or epigastric pain, fat intolerance, and jaundice. Advancement of symptoms makes it essential for the patient to seek treatment. To date, cholecystectomy (surgical removal of gallbladder along with gallstone) is the gold standard. A study in Germany states the occurrence of more than 170,000 cholecystectomies due to cholelithiasis in a year. A study says that there is a gradual increase in gallstone cases and obviously cholecystectomy due to changing lifestyles. This means gallstone is associated with our metabolism. Ursodeoxycholic acid is pharmacologically preferred, but the result is restricted to cholesterol gallstones. Furthermore, it takes a longer time for the dissolution. Another challenge in the process of gallstone dissolution is its rate of reoccurrence. Reoccurrence sometimes persists in (14% of the cases) common bile duct which has proved morbidity.

There are different methods of diagnosis of gallstones like ultrasound; a further challenge is that the diagnostic method does not predict the types and composition of gallstones. As there are different types of gallstones, the treatment and prevention may vary. Furthermore, it is estimated that only 10% of the total cases of gallstone develop symptoms. This nonsymptomatic occurrence rate marks another level of risk. The persistence of gallstones in the gallbladder for a longer time ruptures the internal cell wall of the gallbladder which further develops cancer. Here, the challenge is that gallbladder is generally detected at the late stage. Various studies state that the chances of survival after the development of gallbladder cancer are from 6 months to one year. Here we have tried to recapitulate the mechanism of gallstone formation, its treatment, and prevention. The genetic predisposition as well as the relation of gallstones and gallbladder cancer has also been investigated. The book will provide a complete reference for researchers to introduce new techniques that can prevent cholecystectomy.

The basic challenge with the gallstone is the variation of the composition of the gallstone based on epidemiological factors. Such variation in the chemical content complicates the treatment process as targeting a specific chemical disruption is challenged. The book will contain a descriptive molecular mechanism for gallstone formation. This could direct the researcher to focus on its mechanism to design a pharmacologically active compound for gallstone treatment. The book would provide all possible factors for gallstone formation in one platform which will be an intriguing factor for the reader and based on those preventative measures can be taken at an early age.

The book has the following appealing points:

1. It is based on the current research methodology.

2. Treatment methods are more focused, including both chemical and herbal methods.

3. The mechanism behind the gallstone formation is appealing to the researchers as this will incite the steps for the introduction of a treatment method that can prevent cholecystectomy.

4. Acute pancreatitis is one of the major concerns as a gastrointestinal disease which is also discussed in this book.

5. Effect of gallstones in cancer-causing mechanisms is another focus of the book.

Chapter 1

Historical perspective of gallstones

Bhavna Sharma¹, Rajani Sharma², Ram Prasad³ and Shubha Rani Sharma¹,    ¹Department of Bioengineering & Biotechnology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India,    ²Department of Biotechnology, Amity University Jharkhand, Ranchi, Jharkhand, India,    ³Department of Botany, School of Life Sciences, Mahatma Gandhi Central University, Motihari, Bihar, India

Abstract

Gallstone is considered the second most prevalent gastrointestinal disease. The history of occurrence, classification, and treatment started long back in the BCE era. It has also been seen in Egyptian Mummies during autopsy. Gallstone was first mentioned in CE 1420 when a woman died of abdominal pain. Till the 18th century, the death rate was high due to gallstones because of the absence of a treatment process. In 1687, gallstone was removed for the first time by surgery, and to date, it is considered the most preferred treatment method. There are different ways to classify them depending on their morphology and composition. We generally consider three types of gallstone; Cholesterol gallstone, pigmented gallstone, and mixed gallstone. The classification system assists in the study of the treatment process and epidemiology behind its formation.

Keywords

Digestive system surgical procedure; metabolic disorder; biochemical analysis; infectious disease; digestive system disorder; medical imaging; pharmaceutical therapy; clinical history finding; diagnostic procedure; gallstone; prevalence of gallstone; classification of gallstone; symptoms

Introduction

Gallstones are considered one of the most challenging gastrointestinal diseases. Gallstones were first mentioned by Antonio Benevieni, a pathologist in 1420 in the case of death due to abdominal pain in a woman. This was followed by recognizing biliary colic which is a pain in the abdominal median region due to obstruction of the bile duct by gallstones. Numerous cases of biliary colic were reported by surgeons and physicians, one of them was Francis Gilson in 1658. Gallstones were accidentally discovered by surgeon Stal Pert Von der Wiel in 1687 during the operation of a patient with purulent peritonitis. However, till the 18th century, no proper treatment was developed for gallstones (Shehadi, 1979). The removal of gallstones and gallbladder drainage was suggested by Jean-Louis Petit, who found surgery on the gallbladder in 1733. Petit had set rigid criteria for the surgery which included stimulating the skin to provoke the gallbladder’s adhesion to the wall of the abdomen and then introducing trocar for removing the stones as well as bile from the gallbladder that is adhered for minimizing peritonitis. However, this criterion was modified over the years. Till 1859, gallbladder surgery was continued then an elective cholecystostomy was suggested by J. L. W Thudichum. First, an incision was made in an inflamed gallbladder to sew it to the anterior of the abdominal wall and for the removal of gallstones this functioned as a route. Dr. John Stough Bobbs, during an operation of an ovarian cyst, discovered an adhered sac having many solid bullets-like structures. The sac was opened by him, and it had multiple gallstones. The gallstones were removed from patients and the gallbladder was left in the abdomen. This led to the recovery of the patient (Traverso, 1976).

The first cholecystostomy was designed and performed by Marion Simms in 1878 on a woman patient who was 45 years old and was suffering from obstructive jaundice. Internal hemorrhage led to the death of this patient on the eighth-day post-operation. After this, Theodor Kocher performed a cholecystostomy which was successful in June 1878. Carl Johann August Langenbuch envisioned finding a permanent solution for gallstones as others were busy with the disease’s product (Hardy, 1993).

Biliary colic was a more prominent problem at that time and surgeons were exposed to it. Langenbuch, who was appointed as a director of the Lazarus Hospital in Berlin, observed many such cases. Also, it was shown experimentally on animals by Teckoff in 1667 and Zambaecarri in 1630 that a gallbladder was not necessary to live. Also, it was believed by physicians that the gallstones were produced by the gallbladder itself. The gallbladder of a 43-year-old man was removed by Langenbuch by cholecystectomy using cadaveric dissection on July 15, 1882 (Shehadi, 1979).

Langenbuch observed a chronically thickened and inflamed gallbladder. After six weeks, the man was discharged uneventfully. Afterward, there was a debate between the new cholecystectomy and the already established one (Traverso, 1976).

In 1886, an audit was performed that reported 39 cholecsytomies having a mortality rate of 27% and 8 cholecystomies having a mortality rate of 12%. By now, many were convinced by cholecystectomy performed by Langenbuch, and in 1897, hundreds of operations were performed that had a mortality rate of less than 20%. Now, it was established that permanent relief from pain can be achieved by this cholecystectomy. The death of Langenbuch occurred due to appendicitis on 9 June, 1901 but he showed the path that led to advancements in biliary surgery (De, 2004).

The preliminary knowledge of the gallstone disease dates to the time of the rule of Egyptian pharaohs. Gallstones were found in the body cavities during the autopsy of mummies (Cárdenas-Arroyo & Martina, 2019).

Gallstones are formed by the deposition of cholesterol and are found in the gallbladder. They were reported in the autopsy studies of the Chinese and Egyptian mummies. Cholesterol gallstones are the most prominent in Western countries. In the case of Asia and other developing nations, pigment and mixed stones are prominent. Except for the presence of gallstones in gallstone disease, there are also symptoms and complications including biliary colic, acute cholangitis, acute cholecystitis, and gallstone pancreatitis (Cárdenas-Arroyo & Martina, 2019). The prevalence of gallstones shows many variations based on environmental and genetic factors while they occur commonly in adults (about 20%) in the United States and Europe. The populations having a higher burden of gallstones are also linked to a higher risk of gallbladder carcinoma. The gold standard in the treatment of gallstones is cholecystectomy and annually 70,000 cholecystectomies are performed in the United States (Shehadi, 1979).

Gallstones have been associated with various complications and symptoms for centuries. The understanding of its clinical associations and natural history is evolving continuously along with the understanding of the benefits and risks of medical and surgical interventions (Berger et al., 2000).

Although in the general population, gallstones are common, and in only some cases, the patients develop symptoms. For deciding the appropriate therapy, these symptoms and complications play a role. Very few studies have been done to estimate the relative risks of the development of the symptoms in patients who were initially asymptomatic. These kinds of studies have been a smaller and wider range of symptoms have been reported (Berger et al., 2000).

In a study conducted based on the population to understand the risk factors for gallstones. Three groups were randomly selected for the study. The duration of the study was 17.4 years and 664 patients had gallstones that were detected by sonography. The higher risks were larger stones of size more than 10 mm, female gender, and having multiple stones. Moreover, age was found to be inversely proportional (Portincasa et al., 2006). The reporting of gallstones in Egyptian mummies shows the existence of this disease during 1000 BCE (Shehadi, 1979). A significant burden on health care is caused by gallstones, which are common in Western countries (Berger et al., 2000; Cárdenas-Arroyo & Martina, 2019; De, 2004; Hardy, 1993; Portincasa et al., 2006; Traverso, 1976).

Earlier the most common notion for gallstones was fertile, female, and forty but now it is changing to female patients who are young and thin, as well as male patients (Berger et al., 2000).

History of gallstone classification

We have not taken into consideration the classification systems that evaluated only the physical characteristics and not chemical parameters. The new classification systems that took into account the physical and chemical analysis and utilized advanced techniques for understanding them were reviewed. The techniques included Fourier Transform Infrared Spectroscopy (FTIR), Field Emission Scanning Electron Microscope (FESEM), etc.

Classification system for gallstone

Former classification of gallstones

The gallstones were classified initially in 1896 by Nauyn into ordinary gallbladder stones, pure cholesterol stones, mixed bilirubin stones, laminated cholesterol stones, and rare forms. The basis of this classification was etiological factors and it utilized the proposition of Tarnoky and Holt. In 1924, the reconsideration of this was done by Aschoff. In 1981, another classification of gallstones came up that the National Institute of Health (NIH) proposed. This was done in a workshop on pigmented gallstone disease (Naunyn, 1896).

The classification of gallstones was done into cholesterol and pigmented gallstones. The subclassification of pigmented gallstones was done into black and brown pigment gallstones. Pickens predicted that in the case of combination gallstone or commonly mixed gallstone, the cholesterol content was 94%, and as the cholesterol concentration was low in dog bile so these stones were soluble in it. In 1935, no significant differences in the chemical composition of cholesterol pigment calcium and cholesterol pigment stones were reported by Ray (Sutor & Wooley, 1969). In 1960, by using Infrared absorption spectroscopy, Chihara classified the gallstones considering their chemical composition such as (Naunyn, 1896) calcium carbonate, cholesterol, calcium phosphate, proteins, and bilirubin’s calcium salt in ratios that were variable. A new system of classification was given having polysaccharide, stearic acid, triglyceride, and calcium stearate also containing the constituents mentioned above. The vast differences between the urban and rural areas of gallstone were also reported. More amount of cholesterol was found in the case of gallstones from urban patients while in rural patients less cholesterol was found with richness in bilirubin’s calcium salt. Variations in the diet were considered the cause of it. In 1964, a classification which was based on visual inspection or morphology was given by Rains in which the classification of gallstones was done into pigment, cholesterol, or mixed stones (Bouchier,