Are gallbladder problems hereditary?

Gallbladder Disease — Are You at Risk?

The gallbladder is a tiny organ located under your liver that most people don’t think too much about. That is, of course, until it develops problems, such as gallbladder disease.

More than 25 million men and women in the United States are affected by gallbladder disease, an umbrella term that includes:

Gallstones Hardened deposits of digestive fluid that can form in your gallbladder. They can range in size from as small as a grain of sand to as large as a golf ball. Gallstones can be painful and cause nausea and vomiting, but often they are asymptomatic and don’t require surgery.

Cholecystitis This inflammation of the gallbladder is often caused by gallstones blocking the tube that leads out of your gallbladder. Other causes include bile duct problems, tumors, serious illness, and certain infections. Cholecystitis can lead to life-threatening complications if left untreated.

Gallbladder cancer A form of cancer that starts in the gallbladder with a group of cells that grow out of control. About 9 out of 10 gallbladder cancers are adenocarcinomas — a cancer that starts in cells with gland-like properties that line many internal and external surfaces of the body.

Gallbladder disease can affect anyone, but some people are more vulnerable than others. You are most at risk of having gallbladder problems if you:

  • Are a woman
  • Are older than 60
  • Have a family history of gallbladder problems
  • Are overweight or obese
  • Have diabetes
  • Take certain medications
  • Are Native American or Mexican American

Risk Factors for Gallbladder Problems Out of Your Control

Gender In all populations of the world, women are twice as likely as men to develop gallstones, according to research published in April 2012 in the journal Gut and Liver. Pregnant women and those taking hormone replacement therapy are more at risk for gallstones because of higher estrogen levels. Too much estrogen can increase cholesterol in the bile and lessen gallbladder movement, increasing the risk of gallstones. The sex difference narrows with increasing age, but is still prevalent.

Genes According to research published in 2013 in Advances in Clinical Chemistry, the tendency to develop gallstones and gallbladder disease often runs in families, indicating there may be a genetic link. Also, a mutation in a gene that controls the movement of cholesterol from the liver to the bile duct may increase a person’s risk of gallstones. Defects in certain proteins may increase the risk of gallbladder disease in some people.

Age Gallstones are 4 to 10 times more frequent in the older population, especially in people over 60. That’s because as you age your body tends to release more cholesterol into bile, which makes it more likely that stones will form in the gallbladder.

Ethnicity Studies have shown a clear association between race and risk of gallbladder problems that cannot be completely explained by environmental factors. Risk varies widely from extremely low (less than 5 percent) in Asian and African populations, to intermediate (10 to 30 percent) in European and Northern American populations, to extremely high (30 to 70 percent) in Native American populations. Native Americans and Mexican Americans are more likely to develop gallstones than other ethnic groups, probably as a result of dietary and genetic factors.

Risk Factors for Gallbladder Problems You Can Change

Although there are a number of things out of your control when it comes to your risk of developing gallbladder problems, you can reduce your risk by maintaining a healthy weight, watching your diet, and paying close attention to how your body reacts to certain medications.

People who are even moderately overweight or obese are at increased risk of gallbladder problems. When you’re overweight, the liver produces too much cholesterol, overloading the bile ducts and increasing the risk for gallstones. Women especially should watch their weight, because studies have found that a lithogenic risk of obesity is strongest in young women; this means they are more likely to develop calculi (buildup of mineral stones in an organ).

Rapid weight loss as a result of fasting or crash diets, and weight cycling — losing and then regaining weight — can increase cholesterol production in the liver, increasing a person’s risk of gallstones. In fasting associated with severely fat-restricted diets, gallbladder contraction is reduced, which can also lead to gallstone formation. But research shows that a shorter overnight fast is protective against gallstones in both men and women.

Diet plays a major role in gallbladder disease because diet influences your weight. People who are overweight and eat a high-fat, high-cholesterol, low-fiber diet are at increased risk of developing gallstones. Exposure to the Western diet (increased intake of fat, refined carbohydrates, and limited fiber content) is a high risk for developing gallstones. And too much heme iron — iron found in meat and seafood — may increase gallstone formation in men.

Coffee consumption seems to lower the risk of gallstone formation, by enhancing gallbladder motility, inhibiting gallbladder fluid absorption, and decreasing cholesterol crystallization in the bile, according to research published in the July–December 2013 issue of the Nigerian Journal of Surgery.

Certain cholesterol-lowering medications, such as Lopid (gemfibrozil) and Tricor (fenofibrate), can increase a person’s risk of gallstones. While these drugs successfully decrease blood cholesterol, they increase the amount of cholesterol in the bile, and thus the chance for gallstones to develop.

Other drugs that may increase the risk of gallstones include Sandostatin (octreotide) and a group of diuretics known as thiazides. Octreotide is used to treat certain hormonal disorders and severe diarrhea caused by cancer tumors. Prolonged use of proton pump inhibitors has been shown to decrease gallbladder function, potentially leading to gallstone formation.

If you are concerned that a medication you are taking may increase your risk of gallbladder disease, talk to your doctor. There may be another medication that will do the same thing without increasing your risk for gallbladder problems.

Other Risk Factors for Gallbladder Problems

In addition to genetic and lifestyle factors, certain medical conditions or surgical procedures can also increase your likelihood of developing gallbladder problems. These include:

Diabetes and metabolic syndrome People with diabetes generally have high levels of fatty acids, which may increase the risk of gallstones. Additionally, gallbladder function is impaired in the presence of diabetic neuropathy, and regulation of hyperglycemia with insulin seems to raise the lithogenic index (risk of developing mineral deposits in the gallbladder that can turn into gallstones). People with diabetes are at risk for developing a type of gallbladder disease called acalculous cholecystitis, meaning gallbladder disease without gallstones.

Crohn’s disease and other medical conditions People with Crohn’s disease, an inflammatory bowel disorder, are also at increased risk of gallbladder disease. There are a few reasons for this, but one of the main ones is that if bile salts are not reabsorbed in the ileum (the end of the small intestine), they pass out of the body. This loss of bile salts means that the liver has fewer bile salts to put into new bile. The new bile becomes overloaded with cholesterol, which can in turn result in gallstones.

In addition, cirrhosis of the liver and certain blood disorders, such as sickle cell anemia, also increase a person’s risk of pigment gallstones, which are gallstones made up of bilirubin instead of cholesterol. Low melatonin levels associated with diabetes could contribute to gallstones as well because melatonin inhibits cholesterol secretion from the gallbladder; melatonin is also an antioxidant that reduces oxidative stress to the gallbladder.

Surgery People who undergo bariatric surgery to lose weight are at increased risk for gallstones. Rapid weight loss in general is a risk factor. According to Bariatric Innovations of Atlanta, gallstone formation can be found in as many as 35 percent of weight loss surgery patients. Organ transplant surgery may also increase the risk of gallstones, and it is not uncommon for some doctors to recommend that their patients have their gallbladder removed before they undergo an organ transplant.

Ways to Prevent Gallbladder Problems

Many factors may increase your risk of developing gallbladder problems. While you can’t do much about your genes or ethnicity, you can watch your weight and eat healthfully: Focus on whole grains, fruits and vegetables, fish, and lean meats. Maintaining appropriate portion size and limiting processed foods and added sugars is also essential to a healthy diet. A study published in July 2016 in the journal Preventive Medicine found that vegetable protein is associated with lower gallbladder disease risk.

Additional reporting by Jamie Putman.

Gallstone Gene Discovered: Gene Variant Causes Two- To Three-fold Increase In Risk

Gallstones tend to be found at high levels within certain families. In particular, studies of twins provide evidence of a genetic component that boosts risk levels. “We reckon that environmental influences, like the wrong diet, are 70 to 80 per cent responsible for the disorder,” explains Lammert who works in the university hospital’s Department I headed by Professor Dr. Tilman Sauerbruch. “The rest is caused by genes.”

Professor Lammert — working together with his colleagues Dr. Frank Gruenhage, Maja Walier and Professor Dr. Thomas Wienker as well as scientists at the University Clinic of Cluj-Napoca in Romania — has been searching for the specific genes involved. And he has succeeded, thanks to a study covering 178 women and men from 84 families. They all suffer from gallstones. In 21.4 per cent of cases the subjects were found to be carrying a particular gene variant. In healthy individuals studied as a control group, this variant also occurred, but only at a frequency of 8.6 per cent.

Cholesterol pump at full speed

“The mutation concerns what is known as the ABCG8-gene,” Dr. Gruenhage explains. “It contains the instructions for building a pump responsible for transporting the blood lipid cholesterol from the liver into the bile ducts.” Most of the gallstones consist to a high degree of crystallised cholesterol. The medical researcher concludes that, “The genetic alteration probably makes the pump run permanently at high speed.”

The researchers now hope that their finding will have positive consequences for prevention and therapy. Professor Lammert thinks that, “It may be possible for certain patients to be helped with drug treatments in future, thus avoiding the need for an operation.” However, the genetic contribution to the common problem of gallstones has not been fully explained by this study: “We believe there are at least three or four other gene variants that increase gallstone risk,” says the medical scientist.

Reference: Hepatology No. 46, 11 July 2007, DOI 10.1002/hep.21847

Study Identifies Common Gene Variants Associated With Gallbladder Cancer

March 5, 2017

Findings lead to clues to causes for highly fatal disease

By comparing the genetic code of gallbladder cancer patients with those of healthy volunteers at nearly 700,000 different locations in the genome, researchers say they have found several gene variants which may predispose individuals to develop the disease.

The findings, published March 6 in The Lancet Oncology, could lead to a better understanding of the causes of this highly fatal condition, which could in turn lead to better treatments for the disease. The work is a collaboration between the Johns Hopkins Bloomberg School of Public Health, the National Cancer Institute and Tata Memorial Cancer Centre in Mumbai, India.

Although gallbladder cancer is rare in most parts of the world, it is far more common among some ethnic groups, such as Native Americans in North America, and in certain geographic regions, including Central and South America and East and Southeast Asia. The 178,000 new cases diagnosed worldwide each year are centered primarily in these high-risk regions.

“Using the latest technologies to look at the causes – notably the genetic underpinnings – of this understudied disease just makes a lot of sense,” says study co-leader Nilanjan Chatterjee, PhD, Bloomberg Distinguished Professor in the Department of Biostatistics at the Bloomberg School and a professor of oncology at the Johns Hopkins Kimmel Cancer Center

The gallbladder is a tiny organ in the abdomen which stores bile, the digestive fluid produced by the liver. When gallbladder cancer is discovered early, the chances for survival are good, but most gallbladder cancers are discovered late as it is difficult to diagnose since it often causes no specific symptoms.

To search for which genes might be important in gallbladder cancer, investigators at the Tata Memorial Centre gathered blood samples from 1,042 patients who were treated at the Centre’s Hospital in Mumbai between Sept. 2010 and June 2015. The researchers also collected blood samples during this time from 1,709 healthy volunteers with no known cancers who were visiting patients at the hospital.

To make the groups comparable, they were matched by their ages, sex and geographic regions in India from which the patients came from.

The scientists then ran these blood samples through a whole genome analysis of common single nucleotide polymorphisms (SNPs), places where the genome between different individuals vary by changes in single nucleotides, the smallest units that make up the genome.

Through a series of biostatistical and bioinformatics analyses, they found highly significant association for multiple DNA variants near two genes — ABCB4 and ABCB1 — known to be involved in moving lipids through the liver, gallbladder and bile ducts. A previous study had associated ABCB4 with the formation of gallstones, a known risk factor for gallbladder cancer. But the new results show for the first time that common inherited variants in this region may predispose individuals to gallbladder cancer itself, independent of gallstone status, Chatterjee says.

The researchers later replicated these results using blood samples gathered from 447 more patients with gallbladder cancer and 470 healthy volunteers from Tata Memorial Hospital and Sanjay Gandhi Postgraduate Institute of Medical Science in Uttar Pradesh, India.

They also ran another analysis to estimate how much variation in gallbladder cancer risk can be explained by the discovery of additional common variants. They say they hope to conduct similar studies of larger groups of people in the future.

“Gallbladder cancer, like many other cancers and complex diseases, is likely to be associated with many genetic markers, each of which may have small effects, but in combination they can explain substantial variation in risk,” Chatterjee says.

The researchers estimate as much as 25 percent of gallbladder cancer risk could be explained by common genetic variants. Although the specific genetic variants the current study has identified explain a small fraction of this risk, the fact that they are in close proximity to genes known to be important for transporting a certain class of lipids from liver to gallbladder could provide an important clue to the cause of the disease.

The team is currently planning to investigate the ABCB4/ABCB1 region in more depth by fully sequencing this region in some of the current study participants to understand whether there are additional risk variants there. They also plan to conduct larger studies to look for additional genes associated with gallbladder cancer. By better understanding the function of the genetic risk variants, as well as by investigating environmental and lifestyle causes, Chatterjee says, researchers might eventually be able to develop new treatments or interventions to prevent this disease from occurring in patients at high risk.

“Common Genetic Variation and Risk of Gallbladder Cancer: A Case-Control Genome Wide Association Study” was written by Sharayu Mhatre, Zhaoming Wang, Rajini Nagrani, Rajendra Badwe, Shubhada Chiplunkar, Balraj Mittal, S. Yadav, Haoyu Zhang, Charles C. Chung, Prachi Patil, Stephen Chanock, Rajesh Dikshit, Nilanjan Chatterjee and Preetha Rajaraman.

This study was supported by intramural funding from the Tata Memorial Centre, intramural funding by the National Institutes of Health’s National Cancer Institute, and by the Department of Biotechnology (DBT), India.

# # #

Media contacts for the Johns Hopkins Bloomberg School of Public Health: Stephanie Desmon at 410-955-7619 or [email protected] and Barbara Benham at 410-614-6029 or [email protected]

Gallstones

In some cases, asymptomatic gallstones are discovered by accident–during testing for another diagnosis. However, when pain persists or happens again and again, your health care provider may want to conduct a complete medical history and physical examination, in addition to the following diagnostic procedures for gallstones:

  • Ultrasound. A diagnostic technique that uses high-frequency sound waves to create an image of the internal organs.

  • Cholecystography. X-ray that shows the flow of contrast fluid through the intestines into the gallbladder.

  • Blood tests. These look for signs of infection, obstruction, jaundice, and/or pancreatitis.

  • Computed tomography scan (also called a CT or CAT scan). A diagnostic imaging procedure that uses a combination of X-rays and computer technology to produce horizontal, or axial, images (often called slices) of the body. A CT scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general X-rays.

  • Endoscopic retrograde cholangiopancreatography (ERCP). A procedure that involves inserting an endoscope (viewing tube) through the stomach and into the small intestine. A special dye injected during this procedure shows the ducts in the biliary system.

  • Sphincterotomy. Opening the muscle sphincter, a ring of muscle around a natural opening that acts like a valve, wide enough so stones can pass into the intestine.

Treatment for gallstones

Specific treatment for gallstones will be determined by your health care provider based on:

  • Your age, overall health, and medical history

  • Extent of the condition

  • Your tolerance of specific medicines, procedures, or therapies

  • Expectations for the course of the condition

  • Your opinion or preference

If the gallstones cause no symptoms, treatment is usually not necessary. However, if pain persists, treatment may include:

  • Gallbladder removal (cholecystectomy). Once removed, the bile flows directly from the liver to the small intestine. Side effects of this may include diarrhea because the bile is no longer stored in the gallbladder.

  • Oral dissolution therapy. Drugs made from bile acid are used to dissolve the stones.

  • Methyl-tert-butyl ether. A solution injected into the gallbladder to dissolve stones.

  • Extracorporeal shockwave lithotripsy (ESWL). A procedure that uses shock waves to break stones up into tiny pieces that can pass through the bile ducts without causing blockages.

  • Contact dissolution therapy. An experimental procedure that involves injecting a drug directly into the gallbladder to dissolve the stones.

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TEXT

A number sign (#) is used with this entry because low phospholipid-associated cholelithiasis (LPAC), referred to here as gallbladder disease-1 (GBD1), is caused by homozygous or heterozygous mutation in the ABCB4 gene (171060) on chromosome 7q21.

Description

In general, gallbladder disease (GBD) is one of the major digestive diseases. GBD prevalence is particularly high in some minority populations in the United States, including Native and Mexican Americans. Gallstones composed of cholesterol (cholelithiasis) are the common manifestations of GBD in western countries, including the United States. Most people with gallstones remain asymptomatic through their lifetimes; however, it is estimated that approximately 10 to 50% of individuals eventually develop symptoms. Significant risk factors associated with GBD are age, female sex, obesity (especially central obesity), lipids, diet, parity, type 2 diabetes (125853), medications, and Mexican American ethnicity. GBD appears to be strongly related to the metabolic syndrome (605552) and/or its major components, such as hyperinsulinism, dyslipidemia, and abdominal adiposity (Boland et al., 2002; Tsai et al., 2004). Infection, specifically by Helicobacter, has been implicated in cholelithiasis and cholecystitis (Silva et al., 2003; Maurer et al., 2005).

Low phospholipid-associated cholelithiasis is a specific form of gallbladder disease characterized by young-adult onset of chronic cholestasis with intrahepatic sludge and cholesterol cholelithiasis. Affected individuals have recurrence of the disorder after cholecystectomy and show a favorable response to treatment with ursodeoxycholic acid (UDCA) (summary by Pasmant et al., 2012).

Mutation in the ABCB4 gene can cause a spectrum of related diseases, including the more severe progressive familial intrahepatic cholestasis-3 (PFIC3; 602347), intrahepatic cholestasis of pregnancy-3 (ICP3; 614972), andoral contraceptive-induced cholestasis (OCIC; see 614972).

Genetic Heterogeneity of Gallbladder Disease

Two major susceptibility loci for symptomatic gallbladder disease have been identified on chromosome 1p in Mexican Americans (GBD2, 609918; GBD3, 609919). In addition, variations in the ABCG8 gene (605460) on chromosome 2p21 confer susceptibility to gallbladder disease (GBD4; 611465).

Clinical Features

Rosmorduc et al. (2001) reported 6 adult patients with gallbladder disease. There were 4 women and 2 men, including a mother and son. Common features were adult onset of symptoms related to chronic cholestasis and biliary pain, including biliary colic, pancreatitis, or cholangitis, recurrence of symptoms after cholecystectomy, presence of echogenic material in the intrahepatic bile ducts, and prevention of recurrence with UDCA therapy. One of the women first developed symptoms during pregnancy, consistent with ICP3 (614972), and 1 developed symptoms after beginning oral contraception, consistent with OCIC (see 614972). Another woman developed biliary pain, cholesterol gallstones, and sludge in the gallbladder at age 28 years. UDCA treatment was effective. During her first pregnancy at age 32, UDCA was discontinued. During the 24th week of pregnancy, she developed cholestasis and biliary pain and delivered a premature stillborn fetus. After delivery, the cholestasis and symptoms persisted and she underwent cholecystectomy. However, her symptoms recurred and she had increased liver enzymes and multiple intrahepatic gallstones. Treatment with UDCA resulted in remission, and she had a normal subsequent pregnancy and delivery while on UDCA therapy. A 26-year-old man, born of the woman who developed symptoms during pregnancy, developed acute cholangitis associated with multiple intrahepatic and extrahepatic cholesterol gallstones at age 24. He became free of symptoms after cholecystectomy and treatment with UDCA. An unrelated woman underwent cholecystectomy at age 15 years for cholesterol cholelithiasis. She continued to have recurrent episodes of biliary pain and chronic cholestasis, and received relief with UDCA therapy. A 60-year-old man developed biliary pain with cholestasis at age 55 years and underwent cholecystectomy. Liver biopsy showed portal inflammation, extensive fibrosis, and ductular proliferation, which were thought to be secondary to chronic cholestasis. Hepatic bile composition in 2 patients showed a high cholesterol/phospholipid ratio and cholesterol crystals.

Rosmorduc et al. (2003) identified both heterozygous and homozygous ABCB4 gene mutations in 18 (56%) of 32 patients who presented with clinical criteria specific to LPAC. Three independent clinical features were strongly associated with ABCB4 mutations: recurrence of symptoms after cholecystectomy (odds ratio (OR) of 8.5); intrahepatic hyperechoic foci, intrahepatic sludge, or microlithiasis (OR of 6.1); and age less than 40 years at the onset of symptoms (OR of 3.0). No ABCB4 mutations were detected in 2 other groups of patients with classic cholelithiasis.

Ziol et al. (2008) identified 11 patients, including 2 relatives, with chronic anicteric cholestasis associated with ABCB4 mutations. Six of 11 patients had had biliary symptoms, but only 4 patients met the full criteria for LPAC. The remaining patients were studied because of elevated liver enzymes. One woman had ICP and 2 had oral contraceptive-induced cholestasis. Compared to patients with cholestasis without ABCB4 mutations, patients with mutations had increased hepatic fibrosis, increased ductular reaction, and increased portal infiltration by macrophages on liver biopsy. Mutation carriers also showed decreased immunostaining for ABCB4. Cirrhosis was not observed. Ziol et al. (2008) concluded that unexplained anicteric cholestasis should be added to the spectrum of manifestations associated with ABCB4 mutations.

Pasmant et al. (2012) reported 2 large families with LPAC. In 1 family, the proband presented at age 24 years with intrahepatic cholelithiasis with biliary pain. Despite cholecystectomy, she had recurrence of biliary pain and increased liver enzymes. Treatment with UDCA resulted in complex symptom relief and normalization of liver enzymes. Two paternal relatives had similar symptoms, with a later onset around age 60 years. Liver biopsy in 1 showed carcinoma in situ and bile ductular proliferation. In the second family, the proband presented at age 30 years with cholelithiasis with biliary pain and showed recurrence after cholecystectomy. Her mother, maternal grandmother, and 2 maternal aunts had cholecystectomy before age 40 years.

Inheritance

Nonspecific Gallstone Disease

Reports of familial gallstone disease (e.g., Antero Kesaniemi et al., 1989) and the high incidence of cholesterol gallstones in Native American populations (Weiss et al., 1984) point to genetic factors. Bile from healthy sisters of female gallstone patients has been reported to be more lithogenic than that from controls (Danzinger et al., 1972; Antero Kesaniemi et al., 1989).

Sarin et al. (1995) used ultrasonography to observe the prevalence of gallstone disease in first-degree relatives of patients with cholelithiasis. Three groups were studied: group A, 105 index gallstone patients (male:female, 20:85); group B, 330 first-degree relatives of index patients; and group C, 105 matched controls for group A and 330 for group B. In 39 of 105 (37%) index cases, 1 or more additional family members had gallstones. The index cases with affected relatives were younger than the remaining index cases. Of the 330 first-degree relatives, 51 (15.5%) had gallstones, nearly 4.5 times the frequency in the matched control population (3.6%). No difference was detected in the diet, physical activity, and serum lipid profile between the index patients with affected relatives and those without and between the positive relatives and their controls. Sarin et al. (1995) interpreted the results as an indication that there is a strong familial predisposition for gallstone formation.

Kosters et al. (2003) reviewed the genetic background of cholesterol gallstone disease. The primary pathogenic factor in the multifactorial process of cholesterol gallstone formation is hypersecretion of free cholesterol into bile. They concluded that genetic factors clearly play a role. Analysis of the many pathways involved in biliary cholesterol secretion revealed many potential candidates for identification of ‘gallstone genes.’

In general, gallbladder disease is a complex multifactorial disorder influenced by both genetic and environmental factors. Information on family data suggested that genetic factors play a key role in the development of GBD. Using data from a large Swedish study of 43,141 twin pairs, Katsika et al. (2005) determined that genetic influences are major contributors to the variation in symptomatic gallstone disease. According to this study, genetic factors accounted for 25%, shared environmental factors for 13%, and unique environmental factors for 62% of the phenotypic variance among twins. In addition, varying prevalence on the basis of ethnicity has been considered to be indirect evidence of the genetic determination of GBD. Weiss et al. (1984) proposed that there may be a genetic susceptibility association among complex diseases such as GBD, diabetes, and obesity, which cluster to form a ‘New World syndrome’ in populations with Native American ancestry.

Gallbladder Disease 1/Low Phospholipid-Associated Cholelithiasis

In families with low phospholipid-associated cholelithiasis, Rosmorduc et al. (2001) found evidence for both autosomal dominant and autosomal recessive inheritance.

Molecular Genetics

Rosmorduc et al. (2001) identified 4 different mutations in the ABCB4 gene (171060.0005-171060.0008) in 6 symptomatic adult patients with LPAC. Mutations occurred in both the homozygous and compound heterozygous state. One of the female patients presented during pregnancy, consistent with intrahepatic cholestasis of pregnancy (ICP3; 614972), and another presented after taking oral contraceptives, consistent with oral contraceptive-induced cholestasis (OCIC; see 614972).

Rosmorduc et al. (2003) identified 14 heterozygous or homozygous ABCB4 gene mutations in 18 (56%) of 32 patients who presented with clinical criteria specific to LPAC.

Ziol et al. (2008) identified 8 different mutations in the ABCB4 gene (see, e.g., 171060.0012-171060.0013) in 11 (34%) of 32 patients with chronic unexplained anicteric cholestasis. Eight patients carried a heterozygous mutation, whereas 3 were compound heterozygous for 2 mutations.

In 16 (37%) of 43 adult patients with low phospholipid-associated cholelithiasis, Pasmant et al. (2012) identified heterozygous mutations in the ABCB4 gene. Three (7%) of the 43 patients were found to carry partial or complete deletions affecting the ABCB4 gene. The patients had intrahepatic cholelithiasis despite cholecystectomy before age 40 years. The disorder was associated with cholecystitis, cholangitis, acute pancreatitis, and intrahepatic hyperechoic foci; patients showed a favorable response to UDCA therapy.

Associations Pending Confirmation

Pathogenesis

Defects in the ABCB4 gene compromise the transporter’s ability to move phosphatidylcholine across the canalicular membrane, where it normally would be available for extraction into the canalicular lumen by bile salts. This lack of phospholipid protection in the bile against the detergent effect of the bile salts results in damage to the biliary epithelium, bile ductular proliferation, and potential progressive portal fibrosis. A decreased rate of phospholipid excretion can also be a cause of gallstone formation (summary by Pasmant et al., 2012).

Animal Model

The prevalence of cholesterol gallstones differs among inbred strains of mice fed on a lithogenic diet containing 15% dairy fat, 1% cholesterol, and 0.5% cholic acid. Khanuja et al. (1995) carried out a genetic analysis of the difference in gallstone prevalence rates between a no cholelithiasis strain (AKR) and a high prevalence strain (C57L) by using the AKXL recombinant inbred strain set (AKR x C57L)F1 x AKR backcross mice. Susceptibility to gallstone formation was found to be a dominant trait determined by at least 2 genes: a major gene, named Lith1, mapped to mouse chromosome 2. When examined after 6 weeks on the lithogenic diet, the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (142910; EC 1.1.1.88) was downregulated as expected in the gallstone-resistance strains, AKR and SJL, but this enzyme failed to downregulate in C57L and SWR, the gallstone-susceptible strains. This suggested to Khanuja et al. (1995) that regulation of the rate-limiting enzyme in cholesterol biosynthesis may be pivotal in determining the occurrence and severity of cholesterol hypersecretion and hence lithogenicity of gallbladder bile. The studies indicated that genetic factors are critical in determining gallstone formation and that the mouse model may permit identification of those genetic factors.

Gallstones: Watch and wait, or intervene?

The prevalence of gallstones is approximately 10% to 15% of the adult US population. 1,2 Most cases are asymptomatic, as gallstones are usually discovered incidentally during routine imaging for other abdominal conditions, and only about 20% of patients with asymptomatic gallstones develop clinically significant complications. 2,3

Nevertheless, gallstones carry significant healthcare costs. In 2004, the median inpatient cost for any gallstone-related disease was $11,584, with an overall annual cost of $6.2 billion. 4,5

Laparoscopic cholecystectomy is the standard treatment for symptomatic cholelithiasis. For asymptomatic cholelithasis, the usual approach is expectant management (“watch and wait”), but prophylactic cholecystectomy may be an option in certain patients at high risk.

CHEMICAL COMPOSITION

Gallstones can be classified into 2 main categories based on their predominant chemical composition: cholesterol or pigment.

Cholesterol gallstones

About 75% of gallstones are composed of cholesterol. 3,4 In the past, this type of stone was thought to be caused by gallbladder inflammation, bile stasis, and absorption of bile salts from damaged mucosa. However, it is now known that cholesterol gallstones are the result of biliary supersaturation caused by cholesterol hypersecretion into the gallbladder, gallbladder hypomotility, accelerated cholesterol nucleation and crystallization, and mucin gel accumulation.

Pigment gallstones

Black pigment gallstones account for 10% to 15% of all gallstones. 6 They are caused by chronic hemolysis in association with supersaturation of bile with calcium hydrogen bilirubinate, along with deposition of calcium carbonate, phosphate, and inorganic salts. 7

Brown pigment stones, accounting for 5% to 10% of all gallstones, 6 are caused by infection in the obstructed bile ducts, where bacteria that produce beta-glucuronidase, phospholipase, and slime contribute to formation of the stone. 8,9

RISK FACTORS FOR GALLSTONES

Multiple risk factors are associated with the development of gallstones ( Table 1 ).

Age. After age 40, the risk increases dramatically, with an incidence 4 times higher for those ages 40 to 69 than in younger people. 10

Female sex. Women of reproductive age are 4 times more likely to develop gallstones than men, but this gap narrows after menopause. 11 The higher risk is attributed to female sex hormones, pregnancy, and oral contraceptive use. Estrogen decreases secretion of bile salts and increases secretion of cholesterol into the gallbladder, which leads to cholesterol supersaturation. Progesterone acts synergistically by causing hypomobility of the gallbladder, which in turn leads to bile stasis. 12,13

Ethnicity. The risk is higher in Mexican Americans and Native Americans than in other ethnic groups. 14

Rapid weight loss, such as after bariatric surgery, occurs from decreased caloric intake and promotes bile stasis, while lipolysis increases cholesterol mobilization and secretion into the gallbladder. This creates an environment conducive to bile supersaturation with cholesterol, leading to gallstone formation.

Chronic hemolytic disorders carry an increased risk of developing calcium bilirubinate stones due to increased excretion of bilirubin during hemolysis.

Obesity and diabetes mellitus are both attributed to insulin resistance. Obesity also increases bile stasis and cholesterol saturation.

CLINICAL PRESENTATION OF GALLSTONES (CHOLELITHIASIS)

Most patients with gallstones (cholelithiasis) experience no symptoms. Their gallstones are often discovered incidentally during imaging tests for unrelated or unexplained abdominal symptoms. Most patients with asymptomatic gallstones remain symptom-free, while about 20% develop gallstone-related symptoms. 2,3

Gallstones

  • What is Gallstones
  • Statistics on Gallstones
  • Risk Factors for Gallstones
  • Progression of Gallstones
  • Symptoms of Gallstones
  • Clinical Examination of Gallstones
  • How is Gallstones Diagnosed?
  • Prognosis of Gallstones
  • How is Gallstones Treated?
  • Gallstones References

What is Gallstones

Gallstone disease is a disease of the gall bladder. Gallstones are solid “stones” which are formed from concretions within the gallbladder.

They are two main types: Cholesterol stones (80%), and pigment stones (20%). Pigment stones are composed of bilirubin, the byproduct of haemoglobin (a component in red blood cells) breakdown.

Statistics on Gallstones

Gallstones are present in approxiamately 10-20% of the population. Gallstones may be present at any age but are unusual before the third decade. There is a progressive increase with age, and in patients over 50 the prevalence ranges between 25-30%.

The prevalence is two to three times higher in women than in men. The third National Health and Nutrition Examination Survey estimated that there are 6.3 million men and 14.2 million women aged 20 to 74 in the United States with gallbladder disease.

Risk Factors for Gallstones

Risk factors for cholesterol stones include:

  • High serum cholesterol levels,
  • Increased age,
  • Female sex,
  • Pregnancy,
  • Multiparity,
  • Obesity,
  • Rapid weight loss,
  • Contraceptive pill,
  • Hormone replacement therapy,
  • Ileal disease and resection,
  • Diabetes mellitus,
  • Liver cirrhosis,
  • Gallbladder stasis,
  • Decreased physical activity,
  • Crohn’s disease and
  • Total parenteral nutrition.

Risk factors for pigment stones include:

  • Chronic hameolysis (red blood cell breakdown)
  • Hereditary spherocytosis,
  • Sickle cell disease, as well as
  • Liver cirrhosis.

They may also form in the bile ducts after cholecystectomy (surgical removal of the gallbladder).

There are a few drugs that promote the formation of gallstones:

  • Oestrogen
  • Oral contraceptives
  • Octreotide
  • Clofibrate
  • Ceftriaxone – this is a major cause of biliary sludge in hospitalised patients.

There are several protective factors against gallstone formation:

  • Ascorbic acid
  • Coffee
  • Vegetable protein
  • Poly- and mono-unsaturated fats

Progression of Gallstones

Gallstones are asymptomatic in most patients. They are usually an incidental finding on abdominal radiography. Around 2-4% of patients will experience biliary pain during the first 5 years and then this decreases to 1% per year after that.

After a first attack, as many as half of these patients will have recurrent episodes within 2 years of their first attack and thus elective surgical removal (cholecystectomy) of the gallbladder is recommended for symptomatic patients.

How is Gallstones Diagnosed?

Gallstones that does not cause symptoms cannot be detected by routine laboratory tests.

  • An ultrasound: is the method of choice for identifying gallstones (also for gallstone complications).
  • An x-ray of the tummy – only 10% of gallstones are visible on an x-ray, but this can be useful for excluding alternative diagnoses.

Various tests may be ordered should any complications be suspected (cholecystitis, cholangitis):

  • Full blood count – elevated white cell count, ESR (a test for inflammation in the body) indicating inflammation
  • Liver function tests – biliruibin, evidence of stasis (increased ALP), liver function.
  • Blood cultures – required in the case of cholangitis.
  • Coagulation profile – may be a clotting defect due to poor absorption of vitamin K.

Prognosis of Gallstones

As mentioned above, having one episode of biliary pain means the patient is likely to have futher episodes. However, biliary pain is not necessarily a warning of more complicated disease as the risk of developing complications in symptomatic patients is 1-2% per year and remains steady over time. These can be potentially serious complications and are prevented with a cholecystectomy provided no stones are left in the common bile duct.

How is Gallstones Treated?

For Biliary colic itself – pain relief is all that is required acutely, as well as assessment for complications and to exclude other more serious diagnoses. Sometimes antibiotics are given if infection is suspected.

Cholecystectomy – surgical removal of the gallbladder (usually elective at a later date) is recommended for symptomatic patients. This can be done preferably as a laparoscopic procedure (or known as keyhole surgery) as it has a quicker recovery time and shorter stay in hospital. Cholecystectomy will need to be performed earlier in patients who present with gallbladder inflammation to prevent more serious complications.

For those not suitable for surgery or refuse surgery there are also other options to dissolve or shatter the stones without the need for an operation – although not necessarily as successful as surgery. These include:

  • Dissolution: using acid treatments to dissolve the stones
  • Shock wave therapy: using shock waves to obliterate the stones

Gallstones References

Risk Factors for Gallbladder Cancer

A risk factor is anything that affects your chance of getting a disease such as cancer. Different cancers have different risk factors. Some risk factors, like smoking, can be changed. Others, like a person’s age or family history, can’t be changed.

But having a risk factor, or even many risk factors, doesn’t mean that a person will get the disease. And many people who get the disease may have few or no known risk factors.

Scientists have found some risk factors that make a person more likely to develop gallbladder cancer. Many of these are related in some way to chronic inflammation (long-lasting irritation and swelling) in the gallbladder.

Gallstones are the most common risk factor for gallbladder cancer. Gallstones are pebble-like collections of cholesterol and other substances that form in the gallbladder and can cause chronic inflammation. Up to 4 out of 5 people with gallbladder cancer have gallstones when they’re diagnosed. But gallstones are very common, and gallbladder cancer is quite rare, especially in the US. And most people with gallstones never develop gallbladder cancer.

Porcelain gallbladder

Porcelain gallbladder is a condition in which the wall of the gallbladder becomes covered with calcium deposits. It sometimes occurs after long-term inflammation of the gallbladder (cholecystitis), which can be caused by gallstones. People with this condition have a higher risk of developing gallbladder cancer, possibly because both conditions can be related to inflammation.

Female gender

In the US, gallbladder cancer occurs 3 to 4 times more often in women than in men. Gallstones and gallbladder inflammation are important risk factors for gallbladder cancer and are also much more common in women than men.

Obesity

Patients with gallbladder cancer are more often overweight or obese than people without this disease. Obesity is also a risk factor for gallstones, which might help explain this link.

Older age

Gallbladder cancer is seen mainly in older people, but younger people can develop it as well. The average age of people when they are diagnosed is 72. Most people with gallbladder cancer are 65 or older when it’s found.

Ethnicity and geography

In the US, the risk of developing gallbladder cancer is highest among Mexican and Latin Americans and Native Americans. They are also more likely to have gallstones than members of other ethnic and racial groups. The risk is lowest among African Americans. Worldwide, gallbladder cancer is much more common in India, Pakistan, and Central European and South American countries than it is in the US.

Choledochal cysts

Choledochal cysts are bile-filled sacs along the common bile duct, the tube that carries bile from the liver and gallbladder to the small intestine. (Choledochal means having to do with the common bile duct.) The cysts can grow large over time and may contain as much as 1 to 2 quarts of bile. The cells lining the sac often have areas of pre-cancerous changes, which can progress to gallbladder cancer over time.

Abnormalities of the bile ducts

The pancreas is another organ that releases fluids through a duct into the small intestine to help digestion. This duct normally meets up with the common bile duct just as it enters the small intestine. Some people have a defect where these ducts meet that lets juice from the pancreas flow backward (reflux) into the bile ducts. This backward flow also keeps bile from flowing out of the bile ducts as quickly as it should. People with these abnormalities are at higher risk of gallbladder cancer. Scientists are not sure if the increased risk is due to damage caused by the pancreatic juice or is due to the bile that can’t quickly flow through the ducts causing them to be damaged by substances in the bile itself.

Gallbladder polyps

A gallbladder polyp is a growth that bulges from the surface of the inner gallbladder wall. Some polyps are formed by cholesterol deposits in the gallbladder wall. Others may be small tumors (either cancer or not cancer) or may be caused by inflammation. Polyps larger than 1 centimeter (almost a half inch) are more likely to be cancer, so doctors often recommend removing the gallbladder in patients with gallbladder polyps that size or larger.

Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a condition in which inflammation of the bile ducts (cholangitis) leads to the formation of scar tissue (sclerosis). People with PSC have an increased risk of gallbladder and bile duct cancer. The cause of the inflammation is not usually known. Many people with PSC also have ulcerative colitis, a type of inflammatory bowel disease.

Typhoid

People chronically infected with salmonella (the bacterium that causes typhoid) and those who are carriers of typhoid are more likely to get gallbladder cancer than those not infected. This is probably because the infection can cause gallbladder inflammation. Typhoid is very rare in the US.

Family history

Most gallbladder cancers are not found in people with a family history of the disease. A history of gallbladder cancer in the family seems to increase a person’s chances of developing this cancer, but the risk is still low because this is a rare disease.

Other possible risk factors

Studies have found other factors that might increase the risk of gallbladder cancer, but the links are not as clear. These include:

  • Smoking
  • Exposure to chemicals used in the rubber and textile industries
  • Exposure to nitrosamines

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