**5.5 Effect of rose hip on arthrosis and rheumatoid arthritis**

One of the larger limitations of quality of life in the elderly is osteoarthritis, which is present in more than 60% of people above 50 years of age. Osteoarthritis is often recognized in the hip, knee, spine, or hand and can reduce quality of life from simply

the pain, which occurs from joints where the cartilage is disrupted and also from the inflammation, which can follow the destruction of cartilage.

Limitations in joint movements and pain can reduce the amount of physical activity and in the long run lead to a decline in muscular mass. It becomes more difficult to climb a staircase, ride a bicycle, or to enter a car. This can result in a reduction in social activities and finally a more limited lifestyle [79]. Treatment of osteoarthritis is initially often simply to try and cure symptoms such as pain. First choice of pain cure can be painkillers such as paracetamol and/or nonsteroidal anti-inflammatory agents (NSAIDs). Later on, synthetic opioids (Tramadol) may follow [82]. However, such medication does not repair the reason for pain (cartilage which is destructed). Painkillers only treat symptoms—and on the side—they have side effects such as gastrointestinal bleeding, heart problems, and liver damage [83–87]. Literally, what health professionals are often doing is that they place a bucket on the loft, to catch the water dripping from the destroyed roof instead of repairing the hole in the roof by placing a new roof tile. So, any herbal remedy, which reduces pain and even better also supports the restauration of cartilage, is of high interest in osteoarthritis.

Rheumatoid arthritis is a chronic, inflammatory, and autoimmune disease affecting the joints and also shortening life. Most common symptoms are pain, swollen joints, stiffness of joints, and loss of function. The initial treatment is usually diseasemodifying antirheumatic drugs (DMARDs) often supported with pain killers such as paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs), which as earlier described have side effects. So, any herbal remedy, which can reduce pain and even better support repairment of the body, is of value also in rheumatoid arthritis.

Osteoarthritis is the disease in which rose hip (*Rosa canina*) has been tested the most, as we were able to find a total of six randomized, placebo-controlled, double-blinded clinical studies performed in humans. Five of these studies tested a powdered version of *Rosa canina* subspecies Lito, containing seeds as well as shells dried at very low temperature [23]. The background for this methodology was, as earlier discussed, that heating to more than about normal body temperature might destroy active ingredients in seeds and shells. These five studies focused on osteoarthritis of the hip, knee, and hand. The sixth study was focusing on osteoarthritis of the knee and was based on a product consisting of powdered shells only originating from Chile without any seeds added. The temperature during the preparation procedure was not given, but presumably it was high as most products from Chile are heavily heated [23]. Finally, there was a meta-analysis based on the shell and seed version of rose hip. There were two studies on rheumatoid arthritis, both placebo-controlled and based on the seed and shell version of rose hip.

If not stated, the treatment period was invariably 3 month and the dosage 5 gram daily of powdered rose hip containing seeds and shells served in capsules.

When focusing on osteoarthritis using the combined seed and shell powder, there was a significant reduction in reported pain and stiffness in all five studies [60, 67, 88–90]. In addition, there was also an improvement in general well-being and daily activity such as climbing a staircase, visiting the toilet, or entering a car. The improvement in daily activity was possibly the result of less pain and less stiffness in joints [60, 67, 88–90]. It is interesting to note that in four of the five studies, one study [60] was presented as a dose finding study, indicating dose dependency, there was a significant reduction in the consumption of rescue medication such as paracetamol, tramadol, or NSAIDs [67, 88–90]. This is of some interest as the volunteers in all studies were told not to change the consumption of rescue medication—even though they did so.

See details in **Figure 7**.

#### **Figure 7.**

*Delta change in the consumption of 500 mg paracetamol tablets. The delta change is the delta value of the first fourteen days minus that of the last 14 days of a three-month treatment period.*

When testing the shells only powder (2.225 gram daily), there were no impacts on what patients reported on symptoms such as pain, stiffness, daily activity, or quality of life and neither on the consumption of rescue medication. However, some improvements in knee function could be detected when using gait analyzing in a motor function laboratory [63].

A meta-analysis indicated that the Lito rose hip subspecies significantly reduced pain in osteoarthritis and that the effect size was better than what was observed for paracetamol [91] and comparable to what was seen for NSAIDs [92, 93]. Details are shown in **Figure 8**.

One of the two studies on rheumatoid arthritis only lasted for 1 month, and results were not conclusive [94]. The other study lasted for 6 month, and after 3 month there was a statistically significant improvement in daily activity scores, which was maintained also after 6 months of treatment. After 6 months, there was a further statistically significant improvement in patients as well as doctor's evaluation of disease severity and in quality of life using SF questionnaires [61].

In summary: There are strong indications that the combination of seeds and shells from subspecies of *Rosa canina* exerts a reduction in pain and an improvement in daily

#### **Figure 8.**

*Effect size of Rosa canina (Lito) right panel, to that of NSAIDs (mid panel) and that of paracetamol (left panel). It should be recognized that the Effect Size of rose hip is close to three times higher than that of paracetamol.*

function in osteoarthritis and that the same remedy can be of some benefit to sufferers of rheumatoid arthritis [61, 91]. Other subspecies including subspecies from *Rosa rugosa* can have similar effects; this however remains to be established. From the present evidence it seems clear that both shells and seeds are needed as a study on shellsonly did not show any impact on the pain and discomfort reported by patients [63].

However, the biochemical background for the beneficial effects of *Rosa canina* still remains to be fully elucidated. It was encouraging to note that C-reactive protein (CRP) fell in two studies on osteoarthritis [59, 60]. In a study on rheumatoid arthritis, there was a significant reduction in sedimentation rate, an inflammatory marker [61]. Again, no such changes in inflammatory markers were seen testing shells-only powders [62, 63]. From the insight we have today, it seems that a certain molecule, a galactolipid named GOPO, which acts as an anti-inflammatory agent, is important [95]. The high amount of natural vitamin C, present in *Rosa canina*, and easily absorbed [96] can play an important role for restoring collagen. Also, linoleic and alpha-linolenic acids, which contribute to the COX-1 and COX-2 inhibitory effects observed in rose hip together with triterpene acids, can add some clarification [97, 98]. And finally, the reduction in the synthesis of MMP-1 responsible for the breakdown of collagen can play an important role [81].

#### **5.6 Rose hip for managing renal disturbances**

The kidneys can be damaged in diseases such as diabetes and hypertension. In addition, the formation of stones in the kidneys gives rise to painful and dysfunctional condition. Acute kidney injury is defined as a disorder with disruption of kidney function leading to renal failure. Two major reasons for acute kidney injury are inflammation and oxidative stress. A correlation between a reduction in oxidative stress and a reduction in renal failure was observed in a study where rats with induced acute kidney injury were fed *Rosa canina* [99]. Similar results involving ameliorating renal failure were also observed in another group of rats treated with *Rosa laevigata* [100], as well as in rats suffering diabetes [101, 102].

Prevention strategies for avoiding calcium oxalate nephrolithiasis (kidney stones) are important and on demand. *Rosa canina* extracts have been tested and shown to reduce the number of calcium oxalate calculi and prevent nephrolithiasis in treated rats [103]. On the other hand, human studies for the effects of rose hip treatment on kidney dysfunction are lacking. However, it was encouraging to note that serum creatinine, a marker of kidney function, significantly improved in a human study with *Rosa canina* Lito [59].

#### **5.7 Rose hip in liver protection**

As we earlier stated from our search on folk medicines, rose hip has been claimed to act as a detoxifier. So, are there any indications that rose hip can support the liver? Hepatic injury (liver toxicity) is often characterized by lipid peroxidation, the production of free radicals, and a reduction in antioxidant enzyme activity. Among blood analyses, which can describe to what extend the liver is injured, there are serum alanine transaminase (ALT) and serum aspartate transaminase (AST). Due to our lifestyle, which for many include overeating, consumption of high amounts of alcohol and for some people also sometimes the consumption of different versions of medicine—foods and food supplies, which can protect the liver, has drawn increasing attention. In a study on rats where liver injury was induced, *Rosa canina* restored the abovementioned marker enzymes as well as histopathological alteration caused by the injury. The authors of the paper found a reduction in ALT and AST as the result of treatment and suggested that *Rosa canina* may exert its liver restoring capacity from its content of antioxidants and phenolic compounds [104]. In another study on diabetic rats testing the impact of *Rosa rugosa* on accumulation of fat in the liver, there was also a reduction in ALT and AST as the result of treatment together with a reduction in fat accumulation in the liver [105]. In a study on humans, consuming 45 gram daily of powdered *Rosa canina* from the subspecies Lito containing seeds and shells, given for 1 month, did not affect ALT [59]. However, treating 40 g daily of pure seed powder from the same subspecies for a full 3-month period resulted in a statistically significant drop in ALT (personal communication, K. Winther). This may indicate that also compounds related to rose hip seeds can be important when discussing the protection of the liver, and possibly 1 month of treatment is too short a timeframe when testing the impact of an herbal remedy on liver protection in humans.

In conclusion: From the literature available, it seems like different families of rose hip can be of interest when developing a treatment or a diet, which exerts some liver protection.

#### **5.8 Rose hip for treating skin disorders and aging**

Chronic inflammatory skin disorders (dermatitis) are common in humans of all ages, and we all get facial wrinkle as we get older than 50 years of age. Anti-inflammatory

remedies can reduce the numbers and depth of wrinkles. The two main factors that determine aging of the skin are a) aging associated with time and b) aging resulting from exposure to UV, also known as "photo aging." The combination of these two factors results in loss of functionality of the skin as a barrier against "the outer world." Therefore, dryness, wrinkles, and spots (melanomas) occur. Consequently, protecting the aging skin with anti-inflammatory agents and antioxidants is very important [106].

An extraction of the root of *Rosa multiflora* was recently reported to improve dermatitis in an animal model via COX-2 inhibition. *Rosa multiflora* root extract that is rich in tannins was also shown to be antiallergic by lowering the number of eosinophil leucocytes in another animal model [107, 108]. Interestingly, quercetin isolated from *Rosa canina* was found to lower the melanin content in mouse melanoma cells, while oral administration of rose hip reduced skin pigmentation in guinea pigs [109, 110].

One human study demonstrates that a *Rosa canina* subspecies can influence skin wrinkles, the moisture of the skin, as well as skin elasticity [80]. The study was double-blinded and randomized, lasted 8 weeks, and included 34 volunteers. The effects of *Rosa canina* Lito were compared with a well-known antiwrinkle remedy, Astaxanthin. After 8 weeks of treatment, there was a significant reduction in the depth of crow feet wrinkles as the result of oral rose hip treatment. Similarly, skin moisture and skin elasticity were also significantly improved. The impact was comparable with that of Astaxanthin, which is a strong antioxidant containing the carotenoid pigment. Carotenoid pigment is also found in the rose hip preparation used [23], which is a strong antioxidant too, and rich in several xanthins and able to inhibit the synthesis of MMP-1, an enzyme responsible for the breakdown of collagen [81]. Such strong antioxidant may help to protect collagen and elastin from free radicals formed by UV-induced oxidation, which is responsible for skin aging [109, 110]. It is indeed interesting to note that the actual version of rose hip has been documented to improve collagen [81] and symptoms of osteoarthritis [67, 89–91]. In osteoarthritis as well for the skin, collagen plays a very central role. Another aspect of rose hip impact on the skin is GOPO and its anti-inflammatory property [59, 97]. GOPO was shown to inhibit the chemotaxis of neutrophils and the production of interleukins [59]. Inflammation is a key factor of particular interest as UV radiation is known to result in cell destruction and inflammation. Anti-inflammatory agents therefore have their place as a treatment. It should also be remembered that rose hip seeds and oil from these seeds are used to restore burn injury and restore scars in South America. As earlier stated, seeds from rose hip are also rich in poly unsaturated fatty acids (PUFA), among them linoleic acid and alpha linolenic acid [99], both major constituents of the barrier function of the epidermis [111, 112].

When human erythrocytes are stored in a blood bank, they can normally be stored for up to 5 weeks before the hemoglobin starts to leak out through the erythrocyte membranes as an indicator that the membranes are now disintegrating (getting older). Eighteen healthy volunteers were given 45 gram daily of rose hip powder (Lito) containing seeds and shells for 4 weeks and compared with a group of controls. It was shown that the leak of hemoglobin from red cells, in these volunteers, when stored in a blood bank, was significantly reduced because of treatment with rose hip [80]. Details are shown in **Figure 9**. This was evident after 14 days of treatment and remained for the entire treatment period. This indicates that cell membranes from human erythrocytes, when stored in a blood bank, survive longer before they disintegrate if

#### **Figure 9.**

*Hemoglobin is leaking out through the erythrocyte membrane as the result of disintegration over time (aging) of the membrane. If human volunteers are treated Rosa canina this leak of hemoglobin is lowered indicating that membranes are now more resistant to disintegration.*

volunteers have been treated rose hip the latest month before blood sampling. There is improved longevity of the red cell membranes as the result of rose hip treatment.

In summary: rose hip can influence wrinkles, moisture, and elasticity of the skin, as well as add to the longevity of red blood cells stored in a blood bank. The mechanism behind these properties is believed to be dependent on the antioxidant activity, as seen in the ability of rose hip to suppress the activity of matrix metalloproteinase 1 (MMP-1) that is involved in the breakdown of extracellular matrix and in particular, tissue remodeling. The result of MMP-1 suppression is also supportive to collagen. Anti-inflammatory capacity and certain fatty acids that are present in the seeds and shells are also thought to play an important role here.

#### **5.9 Rose hip and diseases related to the gastrointestinal tract**

Antiulcerogenic activity from "folk remedies" has often been reported, and in this connection, *Rose canina* L is also mentioned [113]. An antiulcerogenic effect from *Rosa canina* extracts was discovered in a rat model. It was later shown that *Rosa canina* can prevent gastric mucosa erosion and the associated hemorrhagic ulcer formation [114]. Extracts from the leaf of *Rosa canina* were also reported to have significant antidiarrheal activity, as well as significantly reduce the intestinal transit time in another animal study [115]. In a clinical trial on humans suffering either Morbus Crohn or Ulcerative colitis, it was documented that the combined seed and shell powder from *Rosa canina* (Lito) significantly lowered symptoms from Morbus Crohn but not symptoms from Ulcerative colitis [116]. One reason for that phenomenon can be that the rose hip version used in the experiment could inhibit neutrophil chemotaxis [59]. Excessive neutrophil activity is involved in the pathogenesis of Morbus Crohn.

In conclusion: Rose hip is interesting when focusing on the gastrointestinal tract, especially by impacting the gastro microbiome. However, more clinical studies in humans need to be available before making any conclusions.


**Endoscopic Ultrasonography (EUS) and Gallbladder**

**Endoscopic Ultrasonography (EUS) and Gallbladder**

Amir Houshang Mohammad Alizadeh Amir Houshang Mohammad Alizadeh Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67758

#### **Abstract**

Diseases of the gallbladder commonly manifest as cholelithiasis and gallbladder cancer. Cholelithiasis has become a significant health problem in developed societies, affecting 10–15% of the adult population. Gallbladder polyps are incidentally detected in approximately 4–7% of patients. In addition, other gallbladder problems may also occur, but these are extremely rare: remnant cystic duct, gallbladder anomalies, Mirizzi syndrome, and gallbladder parasites. Endoscopic ultrasound (EUS) is an excellent method for visualizing the bile duct and gallbladder given its proximity when imaging from the duodenum. EUS can be used for evaluation of gallbladder disease that includes investigation of suspected cholelithiasis or biliary sludge, imaging of polypoid lesions of the gallbladder, and diagnosis and staging of gallbladder cancer. This procedure can be helpful to further distinguish benign from malignant or potentially malignant gallbladder polyps and play an important role in determining the treatment strategy for gallbladder polyps. Furthermore, EUS can help in the diagnosis of rarely gallbladder diseases such as remnant cystic duct, gallbladder anomalies, Mirizzi syndrome, and gallbladder parasites. Recent studies have suggested that EUS‐guided gallbladder drainage (EUS‐GBD) can be considered to be an effective emergency treatment for acute cholecystitis patients at high risk for surgery.

**Keywords:** gallbladder, EUS, FNA

## **1. Introduction**

The gallbladder diseases are relatively common. Of these, cholelithiasis is the most common pathology that affects 10–15% of the adult population. Other conditions such as gallbladder polyp are found in about 5% of the global population, while the estimated incidence of gallbladder cancer is approximately two cases per 100,000 population worldwide [1, 2].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The diseases of gallbladder are generally diagnosed by several different imaging methods in the clinic. Endoscopic ultrasonography (EUS) was introduced in 1980 and has developed considerably in the past 30 years. EUS has recently played an increasing role in the diagnosis of gallbladder diseases [1, 3]. Clinical situations in which EUS can be used for evaluation of gallbladder disease include investigation of suspected cholelithiasis or biliary sludge, imaging of polypoid lesions of the gallbladder, and diagnosis and staging of gallbladder cancer. This diagnostic procedure provides high‐resolution images that can improve the diagnosis of gallbladder diseases [1, 4].

It is noteworthy that EUS is an accurate modality for imaging gallbladder structures because of the close proximity of the duodenum to the gallbladder and extrahepatic biliary tree. EUS can differentiate the double‐layered structure of the gallbladder wall and provide higher resolution for imaging small polypoid lesions (<2 cm) with sensitivity to up to 91.7% and specificity to up to 87.7 [1, 4]. Finally, EUS‐guided gallbladder drainage (EUS‐GBD) is recently gaining favor as an attractive alternative for managing acute cholecystitis in high‐ risk patients. The advantages of EUS‐GBD are the avoidance of external drainage (unlike percutaneous transhepatic gallbladder drainage) and the potential for no risk of post‐ERCP (endoscopic retrograde cholangiopancreatography) pancreatitis or cholangitis (unlike transpapillary drainage) [5, 6].

## **2. EUS and gallbladder microlithiasis**

Gallstones (Cholelithiasis) constitute a significant health problem in developed societies, affecting 10–15% of the adult population. Microlithiasis is defined as small stones (radiological invisibility stones less than 5 mm in diameter and/or stones less than 3 mm in diameter) in the gallbladder and is also referred to as sludge, biliary sand, biliary sediment, microcrystalline disease, pseudolithiasis, and reversible choledocholithiasis [7–9].

Transabdominal US is considered the gold standard for evaluation of gallbladder stones that have been shown to have a high sensitivity (about 98%) for the detection of cholecystolithiasis. However, in some patients, this procedure may miss gallstones, particularly those with small gallstones, and a high level of clinical suspicion for cholelithiasis may make additional studies warranted. Detection of the gallbladder microlithiasis because of their small size may be difficult [4, 8]. Microlithiasis in the gallbladder may be undetected by transabdominal ultrasound and rarely detected on other imaging modalities including multidetector computed tomography (CT) and magnetic resonance imaging (MRI). In some patients with microlithiasis, biliary sludge and/or gallstones can be detected by EUS, with its high spatial resolution [9–11].

It is noteworthy that idiopathic pancreatitis is diagnosed in 10–30% of acute pancreatitis episodes. Recent studies have suggested that microlithiasis is a cause of unexplained pancreatitis in up to 75% of patients with an intact gallbladder [11, 12]. Given the high incidence of microlithiasis and/or biliary sludge as a cause of idiopathic pancreatitis and high accuracy of EUS for recognizing these diagnoses, EUS should be considered as a minimally invasive highly accurate diagnostic tool for idiopathic pancreatitis after conventional radiography fails (**Figure 1**).

**Figure 1.** EUS revealed microlithiasis of gallbladder.

The diseases of gallbladder are generally diagnosed by several different imaging methods in the clinic. Endoscopic ultrasonography (EUS) was introduced in 1980 and has developed considerably in the past 30 years. EUS has recently played an increasing role in the diagnosis of gallbladder diseases [1, 3]. Clinical situations in which EUS can be used for evaluation of gallbladder disease include investigation of suspected cholelithiasis or biliary sludge, imaging of polypoid lesions of the gallbladder, and diagnosis and staging of gallbladder cancer. This diagnostic procedure provides high‐resolution images that can improve the diagnosis of

It is noteworthy that EUS is an accurate modality for imaging gallbladder structures because of the close proximity of the duodenum to the gallbladder and extrahepatic biliary tree. EUS can differentiate the double‐layered structure of the gallbladder wall and provide higher resolution for imaging small polypoid lesions (<2 cm) with sensitivity to up to 91.7% and specificity to up to 87.7 [1, 4]. Finally, EUS‐guided gallbladder drainage (EUS‐GBD) is recently gaining favor as an attractive alternative for managing acute cholecystitis in high‐ risk patients. The advantages of EUS‐GBD are the avoidance of external drainage (unlike percutaneous transhepatic gallbladder drainage) and the potential for no risk of post‐ERCP (endoscopic retrograde cholangiopancreatography) pancreatitis or cholangitis (unlike trans-

Gallstones (Cholelithiasis) constitute a significant health problem in developed societies, affecting 10–15% of the adult population. Microlithiasis is defined as small stones (radiological invisibility stones less than 5 mm in diameter and/or stones less than 3 mm in diameter) in the gallbladder and is also referred to as sludge, biliary sand, biliary sediment, microcrystal-

Transabdominal US is considered the gold standard for evaluation of gallbladder stones that have been shown to have a high sensitivity (about 98%) for the detection of cholecystolithiasis. However, in some patients, this procedure may miss gallstones, particularly those with small gallstones, and a high level of clinical suspicion for cholelithiasis may make additional studies warranted. Detection of the gallbladder microlithiasis because of their small size may be difficult [4, 8]. Microlithiasis in the gallbladder may be undetected by transabdominal ultrasound and rarely detected on other imaging modalities including multidetector computed tomography (CT) and magnetic resonance imaging (MRI). In some patients with microlithiasis, biliary sludge and/or gallstones can be detected by EUS, with its high spatial

It is noteworthy that idiopathic pancreatitis is diagnosed in 10–30% of acute pancreatitis episodes. Recent studies have suggested that microlithiasis is a cause of unexplained pancreatitis in up to 75% of patients with an intact gallbladder [11, 12]. Given the high incidence of microlithiasis and/or biliary sludge as a cause of idiopathic pancreatitis and high accuracy

line disease, pseudolithiasis, and reversible choledocholithiasis [7–9].

gallbladder diseases [1, 4].

98 Updates in Gallbladder Diseases

papillary drainage) [5, 6].

resolution [9–11].

**2. EUS and gallbladder microlithiasis**

Overall, the diagnostic yield of EUS in recurrent idiopathic pancreatitis (RIP) varies from 32 to 88%. Chronic pancreatitis, identified by EUS, is emerging as an important and potential cause of RIP, although EUS may be lack of specificity in the diagnosis of chronic pancreatitis if secretin stimulation testing is used as the gold standard. Preliminary observations indicate that EUS may decrease the need for ERCP through the identification of microlithiasis and chronic pancreatitis [11, 13].

## **3. EUS and gallbladder polypoid lesions**

The gallbladder polypoid lesions are relatively common, with a reported prevalence of approximately 3–7% in patients who undergo transabdominal ultrasonography (US).

On US, these masses have an image with similar echogenicity as that of the gallbladder wall, the lesion projects into the lumen, are fixed, and lack an acoustic shadow. Gallbladder polyps are classified as benign or malignant [4, 14]. Cholesterol polyps are most common benign polypoid gallbladder lesions (62.8%), which appear as pedunculated lesions with a granular surface and an internal echo pattern of a tiny echogenic spot or spots, sometimes with echopenic areas. Other polypoid lesions include adenomyomatosis, adenoma, and adenocarcinoma. The poor prognosis of gallbladder carcinoma patients means it is important to differentiate between benign polyps and malignant or premalignant polyps [14, 15].

The development and refinement of diagnostic imaging modalities such as EUS and their widespread application have led to an increase in the coincidental diagnosis of gallbladder polyps. Current recommendations for the management of gallbladder polyps are based largely on polyp size. Gallbladder polyps larger than 10 mm in diameter, particularly among patients more than 50 years of age, are generally indications for cholecystectomy because of the risk of malignancy [4, 14, 16].

Transabdominal ultrasonography (US) has made the detection of gallbladder polyps easier, but the differential diagnosis of polyps less than 20 mm remains difficult. EUS can be helpful to further distinguish benign from malignant or potentially malignant gallbladder polyps, and is superior to transabdominal US for this purpose. Overall, EUS markedly improves the accuracy of the differential diagnosis of gallbladder polyps and is thought to play an important role in determining the treatment strategy for gallbladder polyps [4, 14, 17].

#### **3.1. Adenomyomatoses**

Adenomyomatosis is a non‐inflammatory gallbladder alteration that occurs in middle age patients and the incidence increases with age. Adenomyomatosis of the gallbladder (GA) remains a common entity among benign gallbladder masses, diagnosed in 2–8% of all cholecystectomies in recent studies. The differentiation of GA from gallbladder cancer is still required because of the similarity in the appearance between gallbladder adenomyomatosis and gallbladder cancer, although many studies have reported imaging findings of adenomyomatosis of the gallbladder using US, computed tomography (CT), magnetic resonance imaging (MRI) and EUS [15, 18, 19].

EUS is a minimally invasive imaging method that can provide high quality images of the gallbladder. EUS has been reported to identify gallbladder adenomyomatosis lesions that were missed by routine abdominal ultrasound. However, this procedure may mistakenly misdiagnose gallbladder cancer as adenomyomatosis. This inaccuracy may occur because of the sole presence of multiple microcysts that can also be seen in gallbladder cancer. In addition to this, EUS provides an additional valuable function, which is the ability to perform EUS fine‐needle aspiration of local lymph nodes, although a resectable gallbladder mass suspicious for cancer should not undergo biopsy due to the risk of seeding. Due to the high cost of performing EUS (its relative invasiveness) and the advanced training it requires, ultrasound remains the primary screening method. So, EUS may be unnecessary in patients in whom ultrasonography produces characteristic findings of adenomyomatosis [18–20].

#### **3.2. Gallbladder carcinoma**

Gallbladder carcinoma (GBC) is the fifth most common gastrointestinal malignancy and the most common biliary tract cancer, accounting for 3% of all tumors. Detection and diagnosis of the gallbladder carcinoma in its early stages is hard because it usually has very slight symptoms or is asymptomatic (**Figure 2**). But once the diagnosis is confirmed, most of these patients often have metastasis and invasion. In addition to this, gallbladder carcinoma is not sensitive to radiotherapy

The poor prognosis of gallbladder carcinoma patients means it is important to differentiate

The development and refinement of diagnostic imaging modalities such as EUS and their widespread application have led to an increase in the coincidental diagnosis of gallbladder polyps. Current recommendations for the management of gallbladder polyps are based largely on polyp size. Gallbladder polyps larger than 10 mm in diameter, particularly among patients more than 50 years of age, are generally indications for cholecystectomy because of

Transabdominal ultrasonography (US) has made the detection of gallbladder polyps easier, but the differential diagnosis of polyps less than 20 mm remains difficult. EUS can be helpful to further distinguish benign from malignant or potentially malignant gallbladder polyps, and is superior to transabdominal US for this purpose. Overall, EUS markedly improves the accuracy of the differential diagnosis of gallbladder polyps and is thought to play an impor-

Adenomyomatosis is a non‐inflammatory gallbladder alteration that occurs in middle age patients and the incidence increases with age. Adenomyomatosis of the gallbladder (GA) remains a common entity among benign gallbladder masses, diagnosed in 2–8% of all cholecystectomies in recent studies. The differentiation of GA from gallbladder cancer is still required because of the similarity in the appearance between gallbladder adenomyomatosis and gallbladder cancer, although many studies have reported imaging findings of adenomyomatosis of the gallbladder using US, computed tomography (CT), magnetic resonance

EUS is a minimally invasive imaging method that can provide high quality images of the gallbladder. EUS has been reported to identify gallbladder adenomyomatosis lesions that were missed by routine abdominal ultrasound. However, this procedure may mistakenly misdiagnose gallbladder cancer as adenomyomatosis. This inaccuracy may occur because of the sole presence of multiple microcysts that can also be seen in gallbladder cancer. In addition to this, EUS provides an additional valuable function, which is the ability to perform EUS fine‐needle aspiration of local lymph nodes, although a resectable gallbladder mass suspicious for cancer should not undergo biopsy due to the risk of seeding. Due to the high cost of performing EUS (its relative invasiveness) and the advanced training it requires, ultrasound remains the primary screening method. So, EUS may be unnecessary in patients in whom ultrasonography

Gallbladder carcinoma (GBC) is the fifth most common gastrointestinal malignancy and the most common biliary tract cancer, accounting for 3% of all tumors. Detection and diagnosis of the gallbladder carcinoma in its early stages is hard because it usually has very slight symptoms or is asymptomatic (**Figure 2**). But once the diagnosis is confirmed, most of these patients often have metastasis and invasion. In addition to this, gallbladder carcinoma is not sensitive to radiotherapy

tant role in determining the treatment strategy for gallbladder polyps [4, 14, 17].

between benign polyps and malignant or premalignant polyps [14, 15].

the risk of malignancy [4, 14, 16].

100 Updates in Gallbladder Diseases

**3.1. Adenomyomatoses**

imaging (MRI) and EUS [15, 18, 19].

**3.2. Gallbladder carcinoma**

produces characteristic findings of adenomyomatosis [18–20].

**Figure 2.** Gallbladder carcinoma in EUS: thickness and irregularity in the wall of gallbladder with invasion to duodenal wall.

and chemotherapy. All of these characteristics make gallbladder carcinoma as a highly lethal tumor with a five‐year survival rate of less than 5% [16, 21]. Many of the signs and symptoms of gallbladder carcinoma are nonspecific, so it is more likely to be diagnosed at an advanced stage in patients and is associated with a high mortality rate. It is important the accurate preoperative staging (**Table 1**) of gallbladder carcinoma, because staging is essential to determine the operative approach, and depth of invasion (T stage) closely correlates with prognosis [4, 15].

Considering that survival after simple cholecystectomy for T1 disease is reported to be near 100%. It becomes increasingly necessary for early diagnosis and identifying patients at high risk of gallbladder carcinoma. As mentioned earlier, EUS can be helpful to distinguish benign from malignant or potentially malignant gallbladder polyps (**Figure 3**).

In addition, there has been interest in using EUS for preoperative staging of gallbladder carcinoma because of this procedure allow detailed visualization of the layers of the gallbladder wall [4, 16]. This procedure is more sensitive than transabdominal US and has the added benefit of determining depth of invasion, extent of local disease, and nodal disease. Moreover, diagnostic accuracy of EUS has been shown for T‐stage: Tis‐stage 100%, T1‐stage 75.6%, T2‐stage 85.3%, and T3,4‐stage 92.7%. EUS also adds the possibility of fine needle aspiration (FNA) for tissue diagnosis of the primary as well as lymph nodes, where diagnostic accuracy approaches 100% [16, 21].

Finally, a scoring system to predict malignant gallbladder polyps has been presented. The total EUS score on the basis of coefficient of multivariate analysis has been shown as follows: (maximum diameter in mm) + (internal echo pattern score; where heterogeneous = 4, homogeneous = 0) + (hyperechoic spot score; where presence = − 5, absence = 0). According to EUS scoring system, the specificity, sensitivity, and accuracy for the risk of malignant gallbladder polyps with scores of 12 or higher were reported for 83, 78, and 83%, respectively [4, 15]. Proposed algorithm for management of gallbladder polyps is shown in **Figure 4**.

#### **Primary tumor (T)**

T3, tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure

T4, tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures

#### **Regional lymph nodes (N)**

NX, regional lymph nodes cannot be assessed

N0, no regional lymph node metastasis

N1, metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or portal vein

N2, metastases to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes

#### **Distant metastasis (M)**

M0, no distant metastasis

M1, distant metastasis

**Table 1.** TNM (tumor, node, metastasis) staging of gallbladder carcinoma [4].

**Figure 3.** Mass of gallbladder.

**Figure 4.** Proposed algorithm for management of gallbladder polyps. EUS, endoscopic ultrasound; CECT, contrast‐enhanced computer tomography; FDG PET, fludeoxyglucose positron emission tomography [16].

## **4. EUS and remnant cystic duct**

**Figure 3.** Mass of gallbladder.

**Primary tumor (T)**

102 Updates in Gallbladder Diseases

Tis, carcinoma in situ

organ or structure

**Regional lymph nodes (N)**

**Distant metastasis (M)**

M0, no distant metastasis M1, distant metastasis

TX, primary tumor cannot be assessed T0, no evidence of primary tumor

T1a, tumor invades lamina propria T1b, tumor invades muscle layer

T1, tumor invades lamina propria or muscle layer

NX, regional lymph nodes cannot be assessed N0, no regional lymph node metastasis

**Table 1.** TNM (tumor, node, metastasis) staging of gallbladder carcinoma [4].

T2, tumor invades perimuscular connective tissue; no extension beyond serosa or into liver

T3, tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent

T4, tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures

N1, metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or portal vein N2, metastases to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes

> Postcholecystectomy syndrome (PCS) is a common manifestation in patients with cholecystectomy. Choledocholithiasis, biliary dyskinesia, and dilation of cystic duct remnants are common causes of these symptoms. Cystic duct or gallbladder remnant with or without stones is one of the important causes of postcholecystectomy syndrome [22, 23]. Usually, a cystic duct remnant measuring 1–2 cm in length is left, although remnants can be seen up to 6 cm in length. Stones in the gallbladder remnant after cholecystectomy are difficult to identify [23, 24].

> Recent progress in radiological imaging has greatly improved diagnostic accuracy in detecting the causes of persistence of symptoms in postcholecystectomy patients. Noninvasive methods of imaging such as US, CT scan, MRCP, and ERCP have been used effectively for diagnosis of gallbladder remnant with or without stones in patients complaining of symptoms suggestive of postcholecystectomy syndrome. Nevertheless, diagnosis of residual gallbladder with gallstones remains difficult. EUS is an excellent diagnostic modality in this situation. EUS procedure is indicated in the presence of strong clinical suspicion with a negative finding on abdominal US. Furthermore, EUS has proven feasibility in diagnosing liver and biliary pathologies with sensitivity and specificity of 96.2 and 88.9%, respectively, and has also been shown to be cost effective in preventing a number of ERCPs [24–26].

## **5. EUS and Mirizzi syndrome**

Mirizzi syndrome is the extrinsic compression of the bile duct by a gallstone at the level of the gallbladder neck or at the cystic duct level. Pablo Luis Mirizzi first described the syndrome in 1948 [27, 28]. Mirizzi syndrome occurs in 0.7–2.8% of patients undergoing cholecystectomy. The syndrome represents a diagnostic challenge because standard imaging may fail to demonstrate external compression of the bile duct, and no findings are pathognomonic for Mirizzi syndrome. However, awareness and diagnosis of this syndrome are essential for safe operative intervention due to the high risk of injury to the bile duct during surgical procedures [28, 29].

ERCP is considered as a procedure of choice for diagnosis of Mirizzi syndrome. The radiological manifestations of the syndrome may be misinterpreted as a tumor of the gallbladder or the cystic duct, metastatic disease of the hilum or acute cholecystitis*.* These diseases should be differentiated from Mirizzi syndrome by a CT scan or an ultrasound. EUS images depicting Mirizzi syndrome are rare [28, 30]. However, very few studies use EUS as a diagnostic method for this syndrome. This seemed strange because EUS is a procedure that allows the observation of the complete bile duct. Furthermore, EUS adequately evaluates the condition of the whole gallbladder, from the bottom to the cystic duct, which is the place in which Mirizzi specifically locates. Finally, since EUS is less risky and less expensive than ERCP, it is suggested that EUS is used as the first diagnostic procedure to confirm whether or not this syndrome is present [27, 29].

## **6. EUS and gallbladder anomalies**

The gallbladder is affected by a large number of congenital anomalies, which may affect its location, number, size, or form. Congenital abnormalities of the gallbladder and biliary system result from embryonic maldevelopment and are most interesting for the surgeon attempting to identify biliary anatomy at cholecystectomy. Some of gallbladder malformations are very rare and may lead to misdiagnosis. Being difficult to diagnose during routine preoperative studies, these anomalies can provide surgeons with an unusual surprise during laparoscopic surgery [31–33].

Preoperative imaging of patients with anomalies of the gallbladder and biliary tract includes US, CT, MRI, EUS, and ERCP. Anomalies of the number of gallbladder include its agenesis and duplication, which may be difficult to diagnose with the use of ultrasound. Agenesis of the gallbladder is very rare, having a prevalence of 0.007–0.13%. Abdominal CT exposes patients to radiation and might not able to provide detailed anatomy of the gallbladder anomalies compared to magnetic resonance cholangiopancreatography (MRCP). Studies have shown that intraoperative ultrasound and postoperative MRCP or EUS can help in the diagnosis of agenesis or ectopic gallbladder. Overall, it is thought that ultrasonography is the primary imaging modality for gallbladder anomalies with CT, MRI being even more helpful, and the MRCP or EUS providing a more thorough visualization of the biliary tract [31, 34, 35].

## **7. EUS and gallbladder parasites**

**5. EUS and Mirizzi syndrome**

cedures [28, 29].

104 Updates in Gallbladder Diseases

syndrome is present [27, 29].

surgery [31–33].

**6. EUS and gallbladder anomalies**

Mirizzi syndrome is the extrinsic compression of the bile duct by a gallstone at the level of the gallbladder neck or at the cystic duct level. Pablo Luis Mirizzi first described the syndrome in 1948 [27, 28]. Mirizzi syndrome occurs in 0.7–2.8% of patients undergoing cholecystectomy. The syndrome represents a diagnostic challenge because standard imaging may fail to demonstrate external compression of the bile duct, and no findings are pathognomonic for Mirizzi syndrome. However, awareness and diagnosis of this syndrome are essential for safe operative intervention due to the high risk of injury to the bile duct during surgical pro-

ERCP is considered as a procedure of choice for diagnosis of Mirizzi syndrome. The radiological manifestations of the syndrome may be misinterpreted as a tumor of the gallbladder or the cystic duct, metastatic disease of the hilum or acute cholecystitis*.* These diseases should be differentiated from Mirizzi syndrome by a CT scan or an ultrasound. EUS images depicting Mirizzi syndrome are rare [28, 30]. However, very few studies use EUS as a diagnostic method for this syndrome. This seemed strange because EUS is a procedure that allows the observation of the complete bile duct. Furthermore, EUS adequately evaluates the condition of the whole gallbladder, from the bottom to the cystic duct, which is the place in which Mirizzi specifically locates. Finally, since EUS is less risky and less expensive than ERCP, it is suggested that EUS is used as the first diagnostic procedure to confirm whether or not this

The gallbladder is affected by a large number of congenital anomalies, which may affect its location, number, size, or form. Congenital abnormalities of the gallbladder and biliary system result from embryonic maldevelopment and are most interesting for the surgeon attempting to identify biliary anatomy at cholecystectomy. Some of gallbladder malformations are very rare and may lead to misdiagnosis. Being difficult to diagnose during routine preoperative studies, these anomalies can provide surgeons with an unusual surprise during laparoscopic

Preoperative imaging of patients with anomalies of the gallbladder and biliary tract includes US, CT, MRI, EUS, and ERCP. Anomalies of the number of gallbladder include its agenesis and duplication, which may be difficult to diagnose with the use of ultrasound. Agenesis of the gallbladder is very rare, having a prevalence of 0.007–0.13%. Abdominal CT exposes patients to radiation and might not able to provide detailed anatomy of the gallbladder anomalies compared to magnetic resonance cholangiopancreatography (MRCP). Studies have shown that intraoperative ultrasound and postoperative MRCP or EUS can help in the diagnosis of agenesis or ectopic gallbladder. Overall, it is thought that ultrasonography is the primary imaging modality for gallbladder anomalies with CT, MRI being even more helpful, and the

MRCP or EUS providing a more thorough visualization of the biliary tract [31, 34, 35].

Parasitic infections of the biliary tract are a major concern in the tropical and subtropical countries with significant morbidity and mortality. These infections occur most commonly with *Ascaris lumbricoides*, *Clonorchis sinensis*, *Opisthorchis felineus*, and *Fasciola hepatica*. Biliary tree parasites can cause cholecystitis, recurrent cholangitis, biliary obstruction, stone formation, and biliary tree strictures, and some may lead to cholangiocarcinoma. Hence, it is important to be aware of the clinical features, diagnostic modalities, and management strategies for various parasites that infest the biliary tract [36–38].

Ultrasonography, CT, and MRI are not only important in the diagnosis of parasitic biliary diseases but also in the follow‐up and surveillance. Furthermore, ERCP is a highly sensitive procedure to demonstrate the presence of parasites in the biliary tree [39, 40]. This procedure is also used in the therapy of biliary parasitic infestations and carries less morbidity and mortality than the surgical approach. It is noteworthy that EUS may also be helpful in the detection of a mobile worm in the extrahepatic bile duct. This diagnostic method can also be a sensitive imaging modality for the extrahepatic bile duct in real time and may be useful for the diagnosis of biliary fascioliasis. Overall, several studies have shown that EUS may be helpful in the diagnosis of parasites in the biliary tract including *Fasciola hepatica* and *Ascaris* [40–42].

## **8. EUS‐guided gallbladder drainage**

Acute cholecystitis is defined as an acute inflammation of the gallbladder wall, regardless of the cause. It results from obstruction to the cystic duct secondary to multiple causes, of which cholelithiasis is the most common followed by benign or malignant biliary strictures. The first line management of acute cholecystitis remains cholecystectomy for patients with good operative candidates. However, early surgical management in elderly patients, those with multiple comorbidities, and those with severe cholecystitis is associated with increased morbidity and mortality [43–45].

Percutaneous transhepatic gallbladder drainage (PTGBD) has been considered the preferred method for several decades in patients with high surgical risk. Although PTGBD has a technical success of nearly 97%, clinical response rates range from 56 to 100% and is also associated with adverse events as high as 14%. PTGBD may be inappropriate for patients with uncorrectable coagulopathy or massive ascites. Moreover, patient discomfort and postprocedure pain have been associated with the percutaneous drainage catheters [46, 47].

Endoscopic gallbladder drainage (GBD) technique includes transpapillary gallbladder stenting, transpapillary gallbladder drainage with nasobiliary drainage (ENGBD), and EUS‐ guided gallbladder drainage (EUS‐GBD). EUS‐GBD is recently gaining favor as an attractive alternative approach for management of acute cholecystitis in high‐risk surgical patients [5, 46]. EUS‐GBD has been performed by using plastic stents, nasobiliary catheters, covered self‐expandable metal stents, and, most recently, lumen‐apposing metal stents (LAMSs). Self‐ expandable metal stents have an advantage over plastic stents because of their ability to seal the gap between the stent and the gallbladder wall, theoretically reducing bile leaks. The perceived advantages of EUS‐GBD are the avoidance of external drainage, internalization of bile, less postprocedure pain (unlike PTGBD), and the potential for no risk of ERCP pancreatitis or cholangitis (unlike transpapillary drainage) [6, 48].

## **9. Conclusion**

EUS is an important new modality for the evaluation of gallbladder disease. This procedure can effectively identify patients with cholelithiasis and gallbladder microlithiasis. Furthermore, studies have shown that EUS can help in the diagnosis of remnant cystic duct, gallbladder anomalies, Mirizzi syndrome, and gallbladder parasites. Polypoid lesions of the gallbladder can be accurately classified by EUS, which can also be safely used to perform FNA to provide a histologic diagnosis. EUS staging of gallbladder carcinoma can help guide therapy and predict prognosis. Recently, EUS‐GBD has become an attractive alternative procedure for management of acute cholecystitis in high‐risk surgical patients.

## **Author details**

Amir Houshang Mohammad Alizadeh

Address all correspondence to<EMAIL_ADDRESS>
Endoscopy Department, Shahid Beheshti University of Medical Sciences, Taleghani Hospital, Tehran, Iran

## **References**

drainage: a promising technique. Annals of Gastroenterology: Quarterly Publication of the Hellenic Society of Gastroenterology. 2016;29(2):162.

[6] Choi JH, Lee SS. Endoscopic ultrasonography‐guided gallbladder drainage for acute cholecystitis: from evidence to practice. Digestive Endoscopy. 2015;27(1):1–7.

the gap between the stent and the gallbladder wall, theoretically reducing bile leaks. The perceived advantages of EUS‐GBD are the avoidance of external drainage, internalization of bile, less postprocedure pain (unlike PTGBD), and the potential for no risk of ERCP pancreatitis or

EUS is an important new modality for the evaluation of gallbladder disease. This procedure can effectively identify patients with cholelithiasis and gallbladder microlithiasis. Furthermore, studies have shown that EUS can help in the diagnosis of remnant cystic duct, gallbladder anomalies, Mirizzi syndrome, and gallbladder parasites. Polypoid lesions of the gallbladder can be accurately classified by EUS, which can also be safely used to perform FNA to provide a histologic diagnosis. EUS staging of gallbladder carcinoma can help guide therapy and predict prognosis. Recently, EUS‐GBD has become an attractive alternative procedure for

Endoscopy Department, Shahid Beheshti University of Medical Sciences, Taleghani Hospital,

[1] Chantarojanasiri T, Hirooka Y, Kawashima H, Ohno E, Kongkam P, Goto H. The role of endoscopic ultrasound in the diagnosis of gallbladder diseases. Journal of Medical

[2] Corwin MT, Siewert B, Sheiman RG, Kane RA. Incidentally detected gallbladder polyps: is follow‐up necessary? Long‐term clinical and US analysis of 346 patients 1. Radiology.

[3] Ko H, Choi I, Chang K, Jeong G, Gong G, Seo H, et al. Amphiphilic metabolites in gallbladder bile: potential biomarkers for gallbladder diseases. Applied Spectroscopy Reviews.

[4] O'Neill DER, Saunders MD. Endoscopic ultrasonography in diseases of the gallbladder.

[5] Patil R, Ona MA, Papafragkakis C, Anand S, Duddempudi S. Endoscopic ultrasound‐ guided placement of the lumen‐apposing self‐expandable metallic stent for gallbladder

Gastroenterology Clinics of North America. 2010;39(2):289–305.

cholangitis (unlike transpapillary drainage) [6, 48].

management of acute cholecystitis in high‐risk surgical patients.

**9. Conclusion**

106 Updates in Gallbladder Diseases

**Author details**

Tehran, Iran

**References**

Amir Houshang Mohammad Alizadeh

Ultrasonics. 2016:1–8.

2011;258(1):277–82.

2016;51(7–9):706–17.

Address all correspondence to<EMAIL_ADDRESS>

[36] Mohamed AE, Al Karawi MA, Ghandour Z. Parasitic disease of the liver and biliary tree. Saudi Journal of Gastroenterology. 1997;3(1):22.

[21] Ejaz A, Sachs T, Kamel IR, Pawlik TM. Gallbladder cancer—current management

[22] Harwani Y, Goenka M, Rai V, Goenka U. Cystic duct remnant stone removal by endoscopic retrograde cholangiopancreatography. Journal of Digestive Endoscopy.

[23] Perera E, Bhatt S, Dogra VS. Cystic duct remnant syndrome. Journal of Clinical Imaging

[24] Mohamadnejad M, Hashemi SJ, Zamani F, Baghai‐Wadji M, Malekzadeh R, Eloubeidi MA. Utility of endoscopic ultrasound to diagnose remnant stones in symptomatic

[25] Chowbey P, Sharma A, Goswami A, Afaque Y, Najma K, Baijal M, et al. Residual gallbladder stones after cholecystectomy: a literature review. Journal of Minimal Access

[26] Topazian M, Salem RR, Robert ME. Painful cystic duct remnant diagnosed by endoscopic ultrasound. The American Journal of Gastroenterology. 2005;100(2):491–5. [27] Gómez MA, Meneses JC. Usefulness of endoscopy for diagnosing Mirizzi syndrome.

[28] Rayapudi K, Gholami P, Olyaee M. Mirizzi syndrome with endoscopic ultrasound

[29] Wilson NA, Wakeman D, Utterson EC, Vogel AM. Intraoperative endoscopic treatment of Mirizzi syndrome in a pediatric patient. Journal of Pediatric Surgery Case Reports.

[30] Aarts M, Engels L. Mirizzi's syndrome. Netherlands Journal of Medicine. 2006;64(7):252–3. [31] Rafailidis V, Varelas S, Kotsidis N, Rafailidis D. Two congenital anomalies in one: an ectopic gallbladder with phrygian cap deformity. Case Reports in Radiology. 2014;2014.

[32] Shaffer E, Romagnuolo J, Thomson A, Shaffer E. The biliary system. Thomson ABR, Shaffer EA First Principles of Gastroenterology: The Basis of Disease and an Approach

[33] Carbajo MA, Martin del Omo J, Blanco JI, Cuesta C, Martin F, Toledano M, et al. Congenital malformations of the gallbladder and cystic duct diagnosed by laparoscopy:

[34] Al Rawahi A, Al Azrii Y, Al Jabril S, Alfadlil A, Al Aghbaril S. Duplicate Gallbladder:

[35] Mittal AK, Saxena D, Kadam R, Garg P, Kankaria J, Jenaw R. Agenesis of gallbladder: a diagnostic dilemma. International Journal of Case Reports and Images (IJCRI). 2015;

overview and Management Challenges. Clinical Surgery. 2016;1:1016.

options. Oncology & Hematology Review. 2013;9(2).

patients after cholecystectomy. Endoscopy. 2014;46(08):650–5.

Revista Colombiana de Gastroenterologia. 2010;25(3):312–5.

image. Case Reports in Gastroenterology. 2013;7(2):202–7.

to Management. Fifth Edition Janssen‐Ortho. 2007:460–90.

high surgical risk. JSLS. 1999;3(4):319–21.

2016;7(2):65.

108 Updates in Gallbladder Diseases

Science. 2011;1:1–4.

Surgery. 2015;11(4):223.

2016;5:8–11.

6(5):296–300.

**Section 5**

**Cholecystectomy**

**Provisional chapter**


**Meet the editors**

Dr. Ricardo Loiola Edvan received his Doctorate in Animal Science from the Ceara Federal University, 2013; his Masters degree in Animal Science from the Paraiba Federal University, 2010; and his Graduate degree in Agronomy from the Ceara Federal University, 2006. He is a Professor in Animal Science, Veterinary and Agronomy courses at the Piaui Federal University, with a

major in Forage and Pastures areas. He is a member of the Animal Science Post-graduate Program in the Piaui Federal University and coordinator of research and technology development projects supported by private and public institutions.

Dr. Edson Mauro Santos received his Doctorate in Animal Science from the Vicosa Federal University, 2007; his Masters degree in Animal Science from the Rural Rio de Janeiro Federal University, 2002; and his Graduate degree in Animal Science from the Rural Rio de Janeiro Federal University, 2006. He is an Animal Science Professor at the Paraiba Federal University, with a

major in Forage and Pastures areas. He is a member of the Animal Science Post-graduate Program in the Paraiba Federal University and coordinator of research and technology development projects supported by private and public institutions.

Contents

**Preface VII**

Horn

Ohrtman

Johnson

Sharon A. Clay

V. Nsahlai

**Climate Change 71** Albrecht Glatzle

**Landfill Site 1**

**Western Snowberry Size 19**

Chapter 3 **Forage Yield Estimation with a Process-Based**

Chapter 4 **Mob vs. Rotational Grazing: Impact on Forage Use and**

**Simulation Model 35**

**Artemisia absinthium 53**

Chapter 5 **Domestic Livestock and Its Alleged Role in**

Chapter 6 **Evaluation and Prediction of the Nutritive Value of**

Chapter 1 **Effectiveness of Grassland Vegetation on a Temporary Capped**

Chapter 2 **Mob Grazing Results in High Forage Utilization and Reduced**

Steffen Beck-Broichsitter, Heiner Fleige, Horst Gerke and Rainer

Heidi Reed, Sharon Clay, Alexander Smart, David Clay and Michelle

James R. Kiniry, Sumin Kim, M. Norman Meki and Mari-Vaughn V.

Heidi Reed, Alexander Smart, David E. Clay, Michelle Ohrtman and

**Underutilised Forages as Potential Feeds for Ruminants 87** Mehluli Moyo, Siyabonga T. Bhiya, Masande Katamzi and Ignatius