The Influence of Ursodeoxycholic Acid in Liver Functional Restoration in Obstructive Jaundice after Endoscopic Treatment

CONTENTS

ABBREVIATIONS

ABSTRACT

1 BACKGROUND
1.1 Epidemiology
1.2 The diagnosis of obstructive jaundice
1.2.1 The clinical presentation
1.2.2 Laboratory findings
1.2.3 Imaging examination
1.2.3.1 Transabdominal sonography
1.2.3.2 Endoscopic sonography
1.2.3.3 Computed tomography
1.2.3.4 Magnetic Resonance Cholangiography (MRCP)
1.2.3.5 Endoscopic Retrograde Cholangiography (ERCP)
1.2.3.6 Percutaneous Transhepatic Cholangiopancreatography (PTC)
1.3 Differential diagnosis of jaundice
1.4 Obstructive jaundice- related complications
1.4.1 Intestinal permeability in obstructive jaundice
1.4.2 Hemostasis impairment in patients with obstructive jaundice
1.4.3 Obstructive jaundice and renal dysfunction
1.4.4 Obstructive jaundice and hepatic dysfunction
1.5 Treatment modalities
1.5.1 Endoscopic Retrograde Cholangiopancreatography (ERCP)
1.5.2 Surgical treatment
1.6 Ursodeoxycholic acid and its properties
1.6.1 Mechanisms of action of UDCA
1.6.1.1 Protection by UDCA against cell death induced by cytotoxic bile acids
1.6.1.2 Modulation of the expression of liver transporters and enzyme systems
by UDCA
1.6.1.3 Modulation of cholangiocyte transport and ductular bile flow
by UDCA
1.6.1.4 Immunosuppressive and anti-inflammatory properties of UDCA

2 AIMS AND PURPOSE OF THE RESEARCH
2.1 General aim
2.2 Specific aims

3 METHODS/DESIGN
3.1 Study objectives
3.2 Study design
3.2.1 ERCP procedure
3.2.2 Biochemical testing
3.2.3 Inclusion criteria
3.2.4 Exclusion criteria
3.2.5 UDCA administration
3.2.6 Power of the study
3.2.7 Data sources and search strategy
3.2.8 Outcomes
3.2.9 Randomization
3.2.10 Ethics
3.2.11 Data collection and statistical analysis

4 RESULTS
4.1 The effect of UDCA in relation to gender of patients
4.2 The effect of UDCA in relation to etiology of obstructive jaundice
4.3 The effect of UDCA in relation to age of patients

5 DISCUSSION

6 CONCLUSIONS

7 REFERENCES

ABBREVIATIONS

Abbildung in dieser Leseprobe nicht enthalten

ABSTRACT

Background: The most common causes of obstructive jaundice are choledocholithiasis, strictures of the biliary tract, cholangiocarcinoma, carcinoma of pancreas, pancreatitis, parasites and primary sclerosing cholangitis. When mechanical biliary obstruction is diagnosed, surgical, endoscopic or radiologic intervention is usually recommended. The aim of this study was evaluation of the effect of UDCA in liver functional restoration of patients with obstructive jaundice in the early period after endoscopic intervention. Specific aims consisted on the evaluation of the effect of UDCA in relation to etiology of obstructive jaundice, to gender, and to age of patients.

Methods: In this prospective, randomized, open-labeled, and controlled study, 62 patients were enrolled. After diagnosis, eligible patients with obstructive jaundice who met inclusion criteria were randomly divided in the investigation group (n= 31) in which has been administered UDCA, and in the control group (n= 31). UDCA administration started twenty-four hours after endoscopic treatment. It was administered at 750 mg/day, divided into three daily doses and lasted fourteen days. Serum-testing in patients with obstructive jaundice included determination of bilirubin (total and direct fractions), alanine transaminase (ALT), aspartate transaminase (AST), gama-glutamil transpeptidase (GGT), alkaline phosphatase (ALP), albumin, neutrophil/ lymphocyte ratio (N/L ratio), urea, glucose, and creatinine. These parameters were determined one day prior endoscopic intervention, and on the fifth, tenth, and fifteenth days after endoscopic intervention. The primary outcome measure in this study was bilirubin, alkaline phosphatase, and GGT serum levels decreasing rate. The secondary outcome was assessment liver functional parameters in which, treatment with UDCA, have had greater impact.

Results: The difference of the average values of total and direct bilirubin, between the groups, was statistically significant at day 0 (p<0.05), but at other evaluation days was not statistically significant, while the difference of the average values of ALT, AST, GGT, ALP, N/L ratio, urea, glucose, and creatinine, between the groups, was not statistically significant (p>0.05). The difference of the average values of albumin, between the groups, was statistically significant at the days 5, 10, and 15 (p<0.05). The decrease rate of total bilirubin, direct bilirubin, GGT, and N/L ratio, between the day 15 compared to day 0, was higher in the IG than in the CG (total bilirubin; 72.6 % vs 67.6 %, direct bilirubin; 78.1 % vs 71 %, GGT; 71.5 % vs 63.4 %, and N/L ratio; 29 % vs 17 %, respectively), while the decrease rate of ALT, AST, and ALP was higher in the CG than in the IG (ALT; 69.8 % vs 67.7 %, AST; 62.2 % vs 59.5 %, ALP; 50.8 % vs 49 %, respectively). The albumin level, in the IG, between the day 15 compared to day 0, was decreased 3.9%, while in the CG the albumin level was increased 5.4%. The levels of urea and creatinine were increased in both groups, but the difference of the average values of these parameters, between the groups, was not statistically significant. The increase rate of urea was higher in the CG than in the IG (22.6 % vs 8.1 %, respectively), while creatinine was higher in the IG than in the CG (14.7 % vs 13 %, respectively).The difference between the average values of all parameters according gender (female vs male) was not statistically significant in the IG (p>0.05). Gender had no significant impact on the values of total and direct bilirubin at all evaluation days in the IG, but had in the CG (p= 0.022365; p= 0.038479, respectively). Also, gender had no significant impact on the values of ALT, AST, GGT, ALP, albumin, N/L ratio, urea, glucose, and creatinine in both groups. On the other hand, etiology had a significant impact on the values of total bilirubin, direct bilirubin, ALP, and N/L ratio in the two groups (total bilirubin: p= 0.003774; p= 0.000533, direct bilirubin: p= 0.005922; p= 0.000022, ALP: p= 0.006942; p= 0.012625, N/L ratio: p= 0.014420; p= 0.000331, respectively). Etiology had a significant impact on the values of AST in the IG (p= 0.004172), but had no in the CG, while had no impact on the values of ALT, GGT, albumin, and creatinine in the groups. Also, etiology had no significant impact on the value of urea in both groups, and had no impact on the glucose in the IG, but had in the CG (p= 0.044487). Patient age had no impact on the values of total bilirubin at all evaluation days in the IG, but had in the CG (p= 0.008696). Age had no impact on the values of direct bilirubin, ALT, AST, GGT, ALP, and glucose in the groups. Also, age had no significant impact on albumin, urea, and creatinine levels and N/L ratio in the IG, but had in the CG (p= 0.010772; p= 0.003102; p= 0.023777; p= 0.001387, respectively).

Conclusions: UDCA has accelerated reducing the level of total bilirubin, direct bilirubin, GGT, and neutrophil/lymphocyte ratio, but did not decrease the level of ALT, AST, and alkaline phosphatase, and did not induce increasing of albumin level. UDCA had greater impact on GGT than in other functional liver parameters. The effect of UDCA did not depend on the gender and the age of patients, but did depend on the etiology of obstructive jaundice. It was more effective in patients with choledocholithiasis than in patients with malign stenosis of biliary tree.

Keywords: obstructive jaundice, ursodeoxycholic acid, treatment with UDCA

1 BACKGROUND

Obstructive jaundice results from biliary obstruction, which is blockage of any duct that carries bile from liver to gallbladder and then to small intestine [1].

The most common causes of obstructive jaundice are choledocholithiasis, strictures of the biliary tract, cholangiocarcinoma, carcinoma of pancreas, pancreatitis, parasites and primary sclerosing cholangitis [2].

Causes of biliary obstruction can be separated into intrahepatic and extrahepatic. Intrahepatic causes are most commonly hepatitis and cirrhosis. Drugs may also cause direct damage to hepatocytes and metabolic obstruction. Causes of hepatitis include viruses, drugs, and alcohol. The majority of cases of cirrhosis in the United States are sequelae of alcoholic hepatitis or chronic hepatitis B and C infections. Drugs, such as anabolic steroids and chlorpromazine, are known to directly cause cholestasis. Amoxicillin/clavulanic acid (Augmentin) is one of the most frequent causes of acute cholestatic injury that can mimic biliary obstruction.

Extrahepatic causes may be further subdivided into those that are intraductal and those that are extraductal. Intraductal causes include stone disease, neoplasms, biliary stricture, parasites, primary sclerosing cholangitis (PSC), AIDS-related cholangiopathy, and biliary tuberculosis. Extraductal obstruction caused by external compression of the biliary ducts may be secondary to neoplasms, pancreatitis, or cystic duct stones with subsequent gallbladder distension. About 95% of biliary strictures are due to surgical trauma and 5% are due to external injury to the abdomen or pancreatitis or erosion of the duct by a gallstone. Stone disease is the most common cause of biliary strictures in patients who have not undergone an operation. Of parasitic causes, adult Ascaris lumbricoides can migrate from the intestine into the bile ducts, thereby obstructing the extrahepatic ducts. Primary sclerosing cholangitis is characterized by diffuse inflammation of the biliary tract, causing fibrosis and stricture of the biliary system. It generally manifests as a progressive obstructive jaundice. Biliary obstruction associated with pancreatitis is observed most commonly in patients with dilated pancreatic ducts due to either inflammation with fibrosis of the pancreas or a pseudocyst. AIDS-related cholangiopathy manifests as abdominal pain and elevated liver function test results, suggesting obstruction. The etiology of this disorder is thought to be infectious (cytomegalovirus, Cryptosporidium species, and microsporidia). Biliary tuberculosis is extremely rare. Stone disease is the most common cause of obstructive jaundice [3, 4]. Stones in the common bile duct occur in 10-15% of patients with gallstones. These stones account for more than 80% of common bile duct stones; they migrate from the gallbladder and are similar appearance and chemical composition to the stones found elsewhere in the biliary tree. Primary bile duct stones may develop infrequently within the common bile duct many years after a cholecystectomy [5].

The prevalence of gallbladder and bile duct stones rises with age [6]. Up to 90% of patients with pancreatic head carcinoma exhibit the signs and symptoms of obstructive jaundice at the time of presentation [7].

1.1 Epidemiology

In the United States the incidence of biliary obstruction is approximately 5 cases per 1000 people. The morbidity and mortality of biliary obstruction depend on the cause of the obstruction. The racial predilection depends on the cause of the biliary obstruction; gallstones are the most common cause of biliary obstruction. Persons of Hispanic origin and Northern Europeans have a higher risk of gallstones compared to people from Asia and Africa.

The sexual predilection depends on the specific cause of the biliary obstruction; women are much more likely to develop gallstones than men. By the sixth decade, almost 25% of American women develop gallstones, with as many as 50% of women aged 75 years developing gallstones. Approximately 20% of men aged 75 years have gallstones, with more complicated disease courses occurring in those who have had cholecystectomies [8].

1.2 The diagnosis of obstructive jaundice

1.2.1 The clinical presentation

The clinical manifestations are dependent on the main etiologies of the disease, and they include the increasing jaundice and abdominal pain for several days, followed by waxing and waning of the pain and jaundice at a background level as the stone disimpacts and reimpacts in the common bile duct, and jaundice with unremitting symptoms, darkening of urine, anorexia, weight loss, and malaise related to malignancies [9].

Regardless of the cause, the physical obstruction causes a predominantly conjugated hyperbilirubinemia. Conjunctival icterus is generally a more sensitive sign of hyperbilirubinemia than generalized jaundice [3].

The lack of bilirubin in the intestinal tract is responsible for the pale stools typically associated with biliary obstruction. The cause of itching (pruritus) associated with biliary obstruction is not clear. Some believe it may be related to the accumulation of bile acids in the skin. Others suggest it may be related to the release of endogenous opioids [4].

1.2.2 Laboratory findings

Regardless of the cause of cholestasis, serum bilirubin values (especially direct) are usually elevated. In the early phases of obstruction and with incomplete or intermittent obstruction, serum bilirubin levels may only be mildly elevated.

Alkaline phosphatase (ALP): A membrane-bound enzyme localized to the bile canalicular pole of hepatocytes, ALP is markedly elevated in patients with biliary obstruction. ALP levels are elevated in nearly 100% of patients, except in some cases of incomplete or intermittent obstruction. Values are usually greater than three times the upper limit of the reference range. An elevation less than three times the upper limit is evidence against complete extrahepatic obstruction.

Gama-glutamil transpeptidase (GGT): These levels are elevated in patients with diseases of the liver, biliary tract, and pancreas when the biliary tract is obstructed. Levels parallel the levels of ALP in conditions associated with cholestasis.

Serum transaminases: (ALT, AST): Levels of these are usually only moderately elevated in patients with cholestasis but occasionally may be markedly increased, especially if cholangitis is present.

Prothrombin time (PT): This may be prolonged because of malabsorption of vitamin K. Correction of the PT by parenteral administration of vitamin K may help distinguish hepatocellular failure from cholestasis. Little or no improvement occurs in patients with parenchymal liver disease [10].

1.2.3 Imaging examination

1.2.3.1 Transabdominal sonography

Ultrasound is the preliminary investigation of choice for the diagnosis of the presence of obstruction and to some extent the level of obstruction. Ultrasonography could pick up the presence of biliary obstruction in 78-98% of cases [11]. Accurate detection of the level of obstruction is possible in 27-95% of cases, and to a much lesser extent the cause of obstruction, about 23-88% of cases. Poor test performance at detecting common bile duct stones with sensitivities 25-58% and specificities 68-91%. Its accuracy ranging is about 47-90% for distinguishing benign from malignant causes. Sensitivities for pancreaticobiliary malignancies range from 5% for ampullary to 67-81% for pancreaticobiliary malignancies [11, 12].

1.2.3.2 Endoscopic sonography

Endoscopic ultrasonography overcomes the limitation of evaluation of distal common bile duct (CBD) by transabdominal sonography. It is very accurate in diagnosing CBD calculi with an overall accuracy of 96% as compared with 63% sensitivity of transabdominal sonography especially with small calculi with non- dilated biliary system [13]. It also picks up small resectable pancreatobiliary mass with high sensitivity, 93-100% [14].

1.2.3.3 Computed Tomography

Traditional computed tomography (CT) scan is usually considered more accurate than ultrasonography for helping determine the specific cause and level of obstruction. The accuracy of conventional CT in determining the presence and level of obstruction has been 81-94% and 88-92% respectively [15]. CT scan has limited value in helping diagnose common bile duct stones because many of them are radiolucent and CT scan can only image calcified stones. CT cholangiography by the spiral CT technique is used most often to image the biliary system and makes possible visualization of radiolucent stones and other biliary pathology [16].

1.2.3.4 Magnetic Resonance Cholangiopancreatography (MRCP) and MRI

MRCP is a non-radiating, non-invasive and yet a highly sensitive method of investigating obstructive lesions of the biliary tract. It has a sensitivity of 95% and specificity of 95% for demonstrating the level and presence of biliary obstruction [17]. MRCP can be considered as the new gold standard for the investigation of biliary obstruction and permits reservation of ERCP to patients with a high probability of therapeutic intervention [18].

1.2.3.5 Endoscopic Retrograde Cholangiopancreatography (ERCP)

ERCP is an outpatient procedure that combines endoscopic and radiologic modalities to visualize both the biliary and pancreatic duct systems. Besides being a diagnostic modality, ERCP has a therapeutic application because obstructions can potentially be relieved by the removal of stones, sphincterotomy, and the placement of stents and drains. The sensitivity and specificity of ERCP are 90% and 98% respectively. Complications of this technique include pancreatitis, perforation, hemorrhage, sepsis, and adverse effects from the drugs used to relax the duodenum. ERCP is still considered the criterion standard for imaging the biliary system, particularly if therapeutic intervention is planned [18].

1.2.3.6 Percutaneous Transhepatic Cholangiopancreatography (PTC)

It is especially useful for lesions proximal to the common hepatic duct. The accuracy of PTC in elucidating the cause and site of obstructive jaundice is 90-100% for causes within the biliary tract [18].

1.3 Differential diagnosis of jaundice

Jaundice is classified into three categories, depending on which part of the physiological mechanism the pathology affects. The three categories are: Pre-hepatic/hemolytic, Hepatic/hepatocellular, and Post-Hepatic/cholestatic jaundice.

Pre-Hepatic jaundice is caused by anything which causes an increased rate of hemolysis. Unconjugated bilirubin comes from the breakdown of the heme pigment found in red blood cells’ hemoglobin. The increased breakdown of red blood cells leads to an increase in the amount of unconjugated bilirubin present in the blood and deposition of this unconjugated bilirubin into various tissues can lead to a jaundiced appearance. Certain genetic diseases, such as sickle cell anemia, spherocytosis, thalassemia, pyruvate kinase deficiency, and glucose 6-phosphate dehydrogenase deficiency can lead to increased red cell lysis and therefore hemolytic jaundice. In jaundice secondary to hemolysis, the increased production of bilirubin leads to the increased production of urine-urobilinogen. Bilirubin is not usually found in the urine because unconjugated bilirubin is not water-soluble, so, the combination of increased urine-urobilinogen with no bilirubin in urine is suggestive of hemolytic jaundice [19].

Hepatocellular jaundice can be caused by acute or chronic hepatitis, hepatotoxicity, cirrhosis, drug-induced hepatitis, alcoholic liver disease, and primary biliary cirrhosis. Cell necrosis reduces the liver’s ability to metabolize and excrete bilirubin leading to a buildup of unconjugated bilirubin in the blood. The unconjugated bilirubin enters the liver cells and becomes conjugated in the usual way. This conjugated bilirubin is then returned to the blood, probably by rupture of the congested bile canaliculi and direct emptying of the bile into the lymph leaving the liver. Thus, most of the bilirubin in the plasma becomes the conjugated type rather than the unconjugated type, and this conjugated bilirubin which did not go to intestine to become urobilinogen gives the urine the dark color [20 - 22]. Post-hepatic jaundice is caused by an interruption to the drainage of bile containing conjugated bilirubin in the biliary system. The most common causes are gallstones, neoplasms, biliary strictures, and pancreatitis. In complete obstruction of the bile duct, no urobilinogen is found in the urine, since bilirubin has no access to the intestine. In this case, presence of conjugated bilirubin in the urine without urine-urobilinogen suggests obstructive jaundice, either intra-hepatic or post-hepatic. The presence of pale stools and dark urine suggests an obstructive or post-hepatic jaundice, although they can occur in many intra-hepatic illnesses and are therefore not a reliable clinical feature to distinguish obstruction from hepatic causes of jaundice [23].

No single test can differentiate between various classifications of jaundice [24]. A combination of liver function tests is essential to arrive at a diagnosis (table1).

Table 1 Diagnostic test for differential diagnosis of jaundice

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1.4 OBSTRUCTIVE JAUNDICE- RELATED COMPLICATIONS

1.4.1 Intestinal permeability in obstructive jaundice

Gastrointestinal tract is not only a passive organ of nutrient absorption, but it additionally displays important endocrine, immunologic, metabolic, and barrier functions. The presence of bile and bile acids in the intestinal lumen is associated with a number of positive effects, contributing to a normal gut barrier function. Bile acids have positive effects in immune, biological, and mechanical barrier. Experimental studies has shown that bile and bile acids affects homing and distribution of T- lymphocytes in the gut-associated lymphatic tissue, and its absence results in decreased numbers of CD4+ and CD8+ T-lymphocytes [25].

Bile acids have been reported to inhibit the growth of certain bacteria such as Bacteroides, Clostridia, Lactobacillus and Streptococci. Absence of bile salts results in a disturbed intestinal bacterial balance with overgrowth of gram negative bacteria [26]. In addition, bile exerts trophic effects on the intestinal mucosa, increasing villous density and inducing hypertrophy of the intestinal wall components [27]. All the components of gut barrier integrity can be affected by biliary obstruction and the absence of bile within the intestinal lumen [25].

Altered intestinal tight junction expression and increased intestinal apoptosis are accompanied by significant alterations of the intestinal oxidative state, which represent an additional important factor in promoting intestinal injury in obstructive jaundice [28, 29]. Increased intestinal permeability has been postulated to be a key factor contributing to bacterial and endotoxin translocation and the pathogenesis of septic and renal complications in patients with extrahepatic biliary obstruction [30].

A suppressed clearance capacity of Kupffer cells, the main hepatic macrophage population, attributed to accumulation of bile acids into liver, permits “spillover” of endotoxin from portal into systemic circulation, with consecutive release of proinflammatory cytokines, potentially leading to the development of the so called “gut derived sepsis” [25].

1.4.2 Hemostasis impairment in patients with obstructive jaundice

As part of the multifactorial role of liver in protein synthesis, many coagulation factors (fibrinogen, prothrombin, V, VII, VIII, IX, X, XI, XII, XIII, prekalikrein), natural anticoagulants (antithrombin-III, heparin cofactor-II, Protein C, Protein S), and compounds of the fibrinolytic system (plasminogen, a2 – antiplasmin) are produced in the liver. A prolonged liver disease, either biliary obstruction or parenchymal liver disease, is consecutively accompanied by abnormal clotting. Bacterial translocation plays a key role in the pathophysiology of hemostasis impairment in patients with obstructive jaundice. The hemostatic derangement in a patient with obstructive jaundice is multifactorial and difficult to assess. An uncomplicated but prolonged benign cholestasis will drive to hemorrhagic diathesis. If septic complications and/or pancreatic involvement are superimposed, the net effect on hemostasis might be a prothrombotic state. When malignancy has been documented, the situation is more complicated. Mucous adenocarcinomas of the pancreas and hepatocellular carcinomas can induce activation of hemostasis. Thromboembolic events, especially in the former, are common and serious complicating events resulting in poor prognosis. Unresolved cholestasis may progressively lead to liver dysfunction and evolution of cirrhosis. In these cases, more generalized hemostatic disorders affecting practically all pathways are observed: thrombocytopenia, decreased synthesis and clearance of coagulation factors and inhibitors, dysfibrinogenemia, hyperfibrinolysis and overt disseminated intravascular coagulation along with portal vein stasis and thrombosis may converge to a single patient [31].

1.4.3 Obstructive jaundice and renal dysfunction

The current evidence, mainly derived from experimental models, indicates that jaundice alone (independent of liver parenchymal disease) affects the integrity of the cardiovascular function. These effects are: 1) reduction in peripheral vascular resistance, which results in systemic hypotension, 2) depression of myocardial performance, and 3) initial and profound natriuresis and diuresis that may lead to volume depletion.

Furthermore, most of the experimental data suggest that neither bilirubin nor bile acids have a direct nephrotoxic effect, and therefore, renal complications in experimental obstructive jaundice are mainly due to prerenal factors. In addition to the deleterious effects of bile acids on the kidney and the circulation, it is clear that factors related to the liver parenchymal damage associated with obstructive jaundice may have an independent contribution to the pathogenesis of “arterial underfilling” which will further predispose these patients to prerenal failure and eventually to acute tubular necrosis.

Clearly, the peripheral and renal hemodynamic effects of “surgical” jaundice are much more marked than that of “medical” jaundice associated with cirrhosis. This difference can be attributed to a higher prevalence and severity of endotoxemia in obstructive jaundice and the deleterious effects of endotoxin on both the peripheral and the renal microcirculation. In addition, the elevated levels of circulating bile acids in obstructive jaundice contribute to a more severe hemodynamic perturbation by a direct effect on the systemic circulation, by a cardiodepressor effect, and probably by a hypovolemic effect [32].

1.4.4 Obstructive jaundice and hepatic dysfunction

Obstructive jaundice can lead to pathophysiologic disorders including functional lesions of the liver and kidney, functional disturbance of blood coagulation, gastric mucous membrane injury, reduced immune function and dysfunction of liver regeneration [33].

Current pathophysiological studies on obstructive jaundice have shown that the damage to the liver, kidney, and immune system of the patients are closely related to endotoxemia [34].

High-grade biliary obstruction begins to cause cell damage, and if it unrelieved may lead to secondary biliary cirrhosis [35]. In obstructive jaundice, increased intestinal permeability has been postulated to be a key factor contributing to bacterial and endotoxin translocation to mesenteric lymph nodes, portal circulation and liver [36].

In patients with obstructive jaundice bile acids can induce liver cells apoptosis. Apoptotic cell death is a highly regulated mechanism that can be viewed as a program of cell suicide vital for a wide variety of biological processes [37]. Cells dying by apoptosis present a number of morphological changes that include chromatin condensation, cytoplasmic shrinkage, membrane blebbing, and the generation of small apoptotic vesicles containing intact cytoplasmic organelles as well as nuclear remnants [37]. Although apoptosis is a highly regulated mechanism, aberrant levels of apoptosis can occur at any time from embryogenesis to adulthood, resulting in a variety of pathological conditions. The apoptotic process may occur by several molecular pathways. The best characterized and most prominent, however, is the intrinsic pathway, involving mitochondria, and the extrinsic pathway, which is activated by death receptors at the cellular membrane [38]. Although apparently independent, these two apoptotic pathways may interact a finely orchestrated crosstalk involving key proteins that are common on both pathways [39].

The mechanisms by which bile acids induce apoptosis in hepatocytes are still not entirely known. It was thought that hydrophobic bile acids, such as glycochenodeoxycholic and taurochenodeoxycholic acids, could induce cytotoxicity by acting as detergents on cell membranes [40]. Indeed, pathophysiological concentrations of bile acids induce apoptosis both by directly activating death receptors [41], and inducing oxidative damage and mitochondrial dysfunction, a combination that strongly sensitizes to apoptosis [42, 43]. Thus, hydrophobic bile acids are unique among naturally occurring apoptotic agents due to their potential to induce apoptosis through both nonspecific detergent effects and receptor-mediated interactions [41].

1.5 Treatment modalities

When mechanical biliary obstruction is diagnosed, surgical, endoscopic or radiologic intervention is usually recommended [26]. The obstructive jaundice syndrome is very common and frequently requires surgical treatment. Its prevalence has increased more than twice since 1980s [44]. Despite advances in preoperative evaluation and postoperative care, intervention, especially surgery, for relief of obstructive jaundice still carries high morbidity and mortality rates, mainly due to sepsis and renal dysfunction [26].

1.5.1 Endoscopic Retrograde Cholangiopancreatography (ERCP)

In the pre-endoscopy and pre-laparoscopic era, the standard treatment for patients suffering from gallstones accompanied with common bile duct stones was open cholecystectomy and common bile duct exploration. With the advent of laparoscopic and endoscopic techniques, several alternative treatments, such as laparoscopic cholecystectomy, preoperative or postoperative endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy and laparoscopic common bile duct exploration, have been developed to treat choledocholithiasis. In the past two decades, laparoscopic cholecystectomy has become gradually accepted as the first choice for the treatment of cholecystolithiasis. Consequently, confirmed or suspected cases of common bile duct stones have been routinely removed via a two-stage management using endoscopic retrograde cholangiopancreatography/ endoscopic sphincterotomy following by laparoscopic cholecystectomy [45].

ERCP is an established diagnostic and therapeutic tool for pancreaticobiliary diseases including choledocholithiasis. However, the diagnostic value of ERCP in biliary diseases, especially benign diseases, has decreased markedly due to inherent invasion. Magnetic Resonance Cholangiopancreatography (MRCP) has gradually become an alternative and is considered to be a noninvasive diagnostic technique in biliary diseases [46].

1.5.2 Surgical treatment

In spite of the advances made in diagnostic procedures over the past several decades, only about 20% of pancreatic cancers are found to be resectable at the time of presentation [47, 48]. In the palliative setting, differentiation between carcinomas of the pancreatic head and the distal biliary tree is often impossible. However, both of these malignancies are usually adenocarcinomas and have the same symptoms when they reach advanced stages. Up to 90% of these patients exhibit the signs and symptoms of obstructive jaundice at the time of presentation [49].

Various palliative therapeutic strategies have been described. Today, the most common treatments are endoscopic biliary stenting and surgical biliary bypass surgery with or without concomitant gastrojejunostomy. In addition, radiologically-guided percutaneous transhepatic biliary drainage or transhepatic stent placement is typically reserved for patients with unresectable disease, and who are unable to undergo endoscopic drainage. The main goal of palliative therapy in patients with unresectable carcinoma of the pancreatic head or distal biliary tree is to resolve the biliary obstruction. There is still disagreement as to whether endoscopic or surgical palliation is associated with a better outcome, and there have been a number of retrospective studies which have shown the superiority of one treatment or the other. The studies have shown that endoscopic stenting has lower morbidity during the initial post-procedural period. However, as the length of follow-up increased in these studies, 20-50% of patients developed complications, such as cholangitis or recurrent jaundice. However, while studies of patients who underwent hepaticojejunostomy found that these patients had higher morbidity rates during the initial postoperative period as well as longer post-procedural hospital stays, the occurrence of long-term sequel such as recurrent jaundice was unusual (0-7%).

Several authors have stated that patient prognosis should guide the decision as to whether surgery or stent placement is more clinically appropriate. They recommended that endoscopic stenting should be performed in patients with a poor prognosis (i.e., a life expectancy less than six months), and that patients with a life expectancy of greater than six months should be treated with biliary bypass because of the better long-term results associated with surgery [50].

1.6 Ursodeoxycholic acid and its properties

From the chemical structural point of view, ursodeoxycholic acid (UDCA) is 3α, 7β- dihidroxy- 5β- cholanoic acid, a bile acid with two hydroxy groups(OHˉ) at positions 3 and 7 in the cholane ring structure, with α and β- orientation respectively [51, 52]. UDCA is a tertiary bile acid which is more and more frequently used in the treatment of different cholestatic diseases. It is normally present in humane bile, but in a low concentration of only 3% of total bile acids. UDCA is the major component of bile acids in black bear bile [53].

UDCA has been used as part of a traditional Chinese medicine from the time of the Tang Dynasty (618-907 AD) for the treatment of jaundice, which employed the bile of black bears to cure several liver diseases. Its therapeutic use was rediscovered many years later by modern medicine, with the first reports on its use in Japan in 1961, followed by the publication of the first controlled trial in patients with primary biliary cirrhosis in 1989 [54].

1.6.1 Mechanisms of action of UDCA

1.6.1.1 Protection by UDCA against cell death induced by cytotoxic bile acids

In cholestatic hepatopathies, bile acids build up inside hepatocytes and, in the case of obstructive cholestasis, in cholangiocytes. Chenodeoxycholic acid (CDCA) and its amide conjugates are the endogenous bile acids that increase the most in chronic cholestatic hepatopathies [55] and thus are the main bile acids involved in the cholestatic damage [51]. Cytotoxic bile acids can differentially induce either necrosis or apoptosis depending on the severity of the cholestasis [56]; necrosis would be the major mechanism of cell death in severe cholestasis, whereas apoptosis would be the predominant one under milder cholestatic conditions [57].

A strong association exists between hepatocellular apoptosis and cholestasis and accumulated bile acids appear to play a key role. Bile-acid-induced apoptosis involves the activatioin of intrinsic and the extrinsic pathways [51].

UDCA and/or its conjugates derivate can protect against hydrophobic bile-acid-induced impairment of mitochondrial function and integrity in hepatocytes, and probably in cholangiocytes, by inhibiting the most important mitochondrial events leading to apoptosis. UDCA inhibits apoptosis induced by compounds other than bile acids. They include the pro-inflammatory cytokines TGF-β1 (transforming growth factor-β1), and TNF-α (tumor necrosis factor-α) [58].Hydrophobic bile acids can induce oncotic necrosis by two main mechanisms, namely oxidative-stress-induced lipid peroxidation and solubilization of the hepatocellular plasma membrane, and both of these can be counteracted by UDCA. As with hepatocytes, cholangiocytes are highly exposed to cytotoxic bile acid levels, as they are also in direct contact with bile. UDCA decreased both nuclear DNA fragmentation and pro-apoptotic protein Bcl-2 levels in biliary epithelial cells [59].

1.6.1.2 Modulation of the expression of liver transporters and enzyme systems by UDCA

UDCA exerts part of its therapeutic effects by reducing the intracellular content/ cytotoxicity of bile acids and other potentially toxic cholephilic compounds accumulated by the secretory failure. At the same time, it favors the elimination of these compounds via alternative routes, mainly the urinary route. This is achieved by: 1) hindering basolateral bile acid uptake, 2) overexpressing basolateral export pumps, and 3) repressing bile acid synthesis and favoring bile acid hydroxylation [60].

1.6.1.3 Modulation of cholangiocyte transport and ductular bile flow by UDCA

Cholangiocyte dysfunction is a common event in many chronic cholestatic diseases and it may play a role in the progression of the disease. Lack of bicarbonates-rich bile secreted at the ductular level may concentrate potentially toxic biliary constituents, and thus contribute to cholangiocyte damage. The distinctive property of UDCA to stimulate bile flow in excess of what is expected from its osmotic properties (hypercholeresis) may contribute to dilute these toxic biliary solutes [61]. UDCA stimulates bicarbonate secretion both in rates and in humans. This is due to its distinctive ability to both undergo cholehepatic shunting and directly stimulate cholangiocyte secretion [62].

1.6.1.4 Immunosuppressive and anti-inflammatory properties of UDCA

In autoimmune cholestatic liver diseases, such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), humoral and cellular immune responses are exacerbated. The former is due to the production of antibodies against certain autoantigens against which the patient has lost immunological tolerance. The latter involves the direct attack of hepatocytes and cholangiocytes by cytotoxic T-lymphocytes, which have been activated by cytokines produced by helper T-lymphocytes, such as interferon-y and interleukin-1 (IL-1), IL-2, IL-4, IL-6.

UDCA is thought to inhibit humoral autoimmunity, as suggested by its ability to suppress the production of IgM, IgG and IgA by B-lymphocytes exposed to bacteria. UDCA also attenuates the cellular immune response by inhibiting the release of cytokines produced by blood mononuclear cells, such as IL-2, IL-4 and interferon-y[62].

2 AIMS AND PURPOSE OF THE RESEARCH

2.1 General aim

The aim of this study was evaluation of the effect of UDCA in liver functional restoration of patients with obstructive jaundice in the early period after endoscopic intervention

2.2 Specific aims

Specific aims were:

- Short term evaluation of the effect of UDCA in relation to the gender of patients
- Short term evaluation of the effect of UDCA in relation to the etiology of obstructive jaundice
- Short term evaluation of the effect of UDCA in relation to the age of patients
- Short term evaluation of liver functional parameters on which UDCA treatment has greater impact in terms of their improvement

3 METHODS/ DESIGN

3.1 Study objectives

This trial was a prospective, open-labeled, randomized, and controlled study. The objective was to evaluate the effect of ursodeoxycholic acid (UDCA) in liver functional restoration in patients with obstructive jaundice in the early post-endoscopic phase.

The study was conducted to the department of abdominal surgery and endoscopy at University Clinical Centre of Kosovo (January 2015- November 2016).

3.2 Study design

After diagnosis, eligible patients with obstructive jaundice who met inclusion criteria were divided into two groups: (A) the investigation group in which has been administered UDCA in the early phase after endoscopic treatment, and (B) control group, in which no treatment has been applied with UDCA.

Diagnostic methods were: Clinical history, biochemical findings, ultrasound examination, endoscopic retrograde cholangiopancreatography (ERCP), CT-scan and magnetic resonance cholangiopancreatography (MRCP).

3.2.1 ERCP procedure

Patients with obstructive jaundice were treated by ERCP. The ERCP procedures were performed with the patient under topical pharyngeal anaesthesia with 2% lidocaine and after administration of sedation (midazolam 2-3 mg). Patients received intravenously infusion of 300 to 500 ml of 0.9 % saline solution and 10 mg Scopolamine butylbromide (Buscopan). The material used to perform ERCP consisted of a video duodenoscope model TJF-Q180F (Olympus), traction sphincterotome, needle scalpel to perform the pre-cut sphincterotomy, hydrophilic guide wire via the bile duct, Dormia basket, ballon catheter for stone extraction, and non-ionic water- soluble contrast 20-40 ml in concentration 1:1 (Omnipaque) for opacification of the biliary and pancreatic ducts. In patients with ductal stones, by ERCP, ductal stones have been extracted. In those with benign or malign strictures, after sphincterotomy and balloon dilatation, procedure was finished by plastic stent (Olympus) application. All patients were monitored continuously during the procedure, with measurements of heart rate, respiratory rate and arterial oxygen saturation.

Patients were kept under surveillance in the endoscopy recovery area for twenty-four hours. They were discharged to home by recommendation to come back for visits and serum-testing of liver biochemical markers on the day 5, 10, and 15 after endoscopic procedure.

3.2.2 Biochemical testing

Serum-testing in patients with obstructive jaundice included determination of bilirubin (total and direct fractions), alanine transaminase (ALT), aspartate transaminase (AST), gama-glutamil transpeptidase (GGT), alkaline phosphatase, albumin, urea, creatinine, glycaemia, and neutrophil- lymphocyte ratio.

The normal values of these biochemical markers are taken as follows : Total bilirubin (5.0- 20.0 µmol/l), direct bilirubin (< 7.0 µmol/l), ALT (<42 U/l), AST (<37 U/l), GGT (M: 11-53 U/l, F: 9-37 U/l), ALP (70-306 U/l), albumin (35-53 g/l), glycaemia (3.8-6.1 mmol/l), urea (2.5-8.3 mmol/l), creatinine (M: 70-108 mmol/l, F: 44-88 mmol/l). These parameters were determined one day prior endoscopic intervention, and on the fifth, tenth, and fifteenth days after endoscopic intervention.

Endoscope procedure that ended with the internal derivation of bile was named as the internal bile drainage.

3.2.3 Inclusion criteria were:

- Patients with obstructive jaundice: choledocholithiasis, benign and malign strictures
- Serum bilirubin level higher than 50µmol/l
- 19+ years of age
- written informed consent

3.2.4 Exclusion criteria were:

- Cholangitis
- Acute pancreatitis
- pregnant women
- women during the breastfeeding
- suspected or proven primary liver diseases
- complications after endoscopic treatment: massive bleeding, acute pancreatitis, cholangitis
- My family members
- Patients who were unable to understand our study purpose

3.2.5 UDCA administration

UDCA administration started twenty-four hours after endoscopic procedure for the patients in the study group and lasted fourteen days. UDCA dose was administered at 750 mg/day, divided into three daily doses.

3.2.6 Power of the study

A clinically relevant improvement of liver functional tests was defined as an improvement of 70% of liver functional tests in test group, and an improvement of 50% in control group. In our study, to have an 80% chance (power= 0.80) of detecting a difference between two groups on improvement of liver functional tests at an alpha level of 0.05, the power calculation indicates that each of the two groups should have at least 31 patients.

3.2.7 Data sources and search strategy

An electronic search was performed on PubMed database (from 1 January 1985 to 1 Septembre 2016). A combination of keywords and MeSH terms where: ‘ursodeoxycholic acid’ AND ‘obstructive jaundice’, ‘obstructive jaundice’ AND ‘liver function tests’, ‘obstructive jaundice’ AND ‘acute renal failure’, “obstructive jaundice” AND “primary biliary cirrhosis”, “obstructive jaundice” AND “ primary sclerosing cholangitis”. I have used , also, limits: Type of article ( selection was- clinical trial, meta-analyses), Species( selection was- human, animals), Text options ( selection was- links to free full text, abstract), Languages( English), Sex ( male, female), Age ( all adult 19+ years), Field ( all fields).

3.2.8 Outcomes

The primary outcome measure in this trial was bilirubin, alkaline phosphatase, and GGT serum levels decreasing rate. The secondary outcome was assessment liver functional parameters in which, treatment with UDCA, have had greater impact. Follow-up measures were collected prior endoscopic intervention, and on the fifth, tenth, and fifteenth days after endoscopic intervention.

3.2.9 Randomization

Patients assigned an informed consent for the involving in the trial on the day of endoscopic procedure before ERCP treatment. Randomization was performed at the time of transfer to the endoscope room according to a random number table, which was established before the study began, using random number generator at http:// www.stattrek.com.

3.2.10 Ethics

This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by Ethics and Professional Committee at the University Clinical Centre of Kosovo. Informed consent was obtained from all participants.

3.2.11 Data collection and statistical analyses

Statistical analysis was made ​​in statistical programs: STATISTICA 7.1; SPSS 17.0: The collected data are processed using the following statistical methods:

-Data Types are formed using specific computer programs for this purpose. Their processing is performed using standard descriptive and analytical methods.
-Qualitative statistical series are analyzed by determining the ratio of relations, proportions, rates and determine the statistical significance between the discovered differences–Difference test.
-The quantitative series are analyzed with measures of central tendency and measures of dispersion of data (mean and standard deviation).
-In numerical series in which there was no deviation from the normal distribution, the significant difference was tested withStudent t- test.
-In numerical series in which there were deviations from the normal distribution, to test the significant difference wasused Mann-Whitney U Test.
-Statistical significance of more than two variables, differences was analyzed with Analysis of Variance - ANOVA. There is a large selection of so-called post hoc tests which are performed after ANOVA-test when it gives statistically significant results. These tests are called test of multiple comparison. Their goal is to understand that differences (between most variables) are responsible for the overall statistically significant results. The study used Post hoc Tukey HSD test.
-ANOVA -Repeated Measures Analysis of Variance were used for measures the parameters which were repeated more than twice.
-The Shapiro-Wilk`s test examined the normal allocation-distribution of variables
-The CI (confidence interval - 95% CI) is defined as statistical significance level of error less than 0, 05 (p).
-The results are presented in tables and figure

4 RESULTS

A total of 96 patients with obstructive jaundice were assessed if they were eligible to participate in the study. Eighteen patients were excluded from the study: serum bilirubin level lower than 50 µmol/l, 10 patients; and declined to participate in the study, 8 patients.

Of the 78 patients enrolled in the study, 40 were randomized in the investigation group (IG) and 38 were randomized to the control group (CG). Of 40 patients randomized to the IG, 31 were completely analysed. Six patients were not presented for further evaluation after discharge, and 3 patients discontinued the investigation: cholangitis, 2 patients; and acute renal failure, 1 patient. Of 38 patients randomized to the control group, 31 were completely analysed. Four patients were not presented for further evaluation after discharge, and 3 patients discontinued the investigation: cholangitis, 1 patient; and consent’s withdrawn, 2 patients (Figure 1). The patients in the test group (investigation group- IG) were treated with ursodeoxycholic acid (UDCA) in the early phase after endoscopic treatment, while the patients in the control group were not treated with UDCA.

The primary cause of the obstructive jaundice was as follows: choledocholithiasis, 31 patients (13 patients in the IG, and 18 patients in the CG); and malign stenosis of extrahepatic biliary tree, 31 patients (18 patients in the IG, and 13 patients in the CG); cholangiocarcinoma, 19 patients; pancreatic cancer, 11 patients; and carcinoma of the ampulla of Vater, 1 patient.

Figure 1 Flow diagram of patients included in the study EMBED Word.Document.8 \s

Table 2 The mean age of patients in both groups and t-test

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IG- investigation group; treatment with UDCA

CG- control group; treatment without UDCA

Figure 2 The mean age of patients in both groups

EMBED STATISTICA.Graph \s

The mean age of patients in the IG was 64.9 years, and in the CG was 57.3 years. According to t-test the difference between the mean age of patients between the two groups was not statistically significant for p> 0.05 (p= 0.058107) (Table 2 & Figure 2).

Table 3 Distribution of patients according to gender in both groups

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Figure 3 Distribution of patients according to gender in both groups

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In the IG females were represented by 58.1% and males by 41.9%. In CG females were represented by 41.9% and males by 58.1%. According Difference test the percentage difference between the genders in both groups was not statistically significant for p> 0.05 (p= 0.2020) (Table 3 & Figure 3).

In the CG stone removal procedure was represented by 58.1% and stent application procedure by 41.9%. In the IG stone removal procedure was represented by 41.9% and stent application procedure by 58.1%. According Difference test the percentage difference between the procedures in both groups was not statistically significant for p > 0.05 (p= 0.2020) (table 4 & Figure 4).

Table 4 Distribution of patients according procedure in both groups

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Figure 4 Distribution of patients according procedure in both groups

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The average value of total bilirubin in patients/IG was 224.2μmol/l at day 0. At day 5 after the procedure was 115.7μmol/l, at day 10 was 82.7μmol/l, and at day 15 was 61.5μmol/l (Table 5 & Figure 5). During the research the index dynamics showed a decrease of total bilirubin level between the day 15 compared to day 0 (72.6%) in the investigation group (IG).

The average value of total bilirubin in patients/CG was 170.2μmol/l at day 0. At day 5 after the procedure was 94.7μmol/l, at day 10 was 70.9μmol/l, and at day 15 was 55.2μmol/l (Table 5 & Figure 5). During the research the index dynamics showed a decrease of total bilirubin level between the day 15 compared to day 0 (67.6%) in the control group (CG).

The difference between the average values was statistically significant for p< 0.05 (p= 0.034706) at day 0. The difference at the other days was not statistically significant for p> 0.05 (Table 6).

The average value of direct bilirubin in patients/IG was 142.1μmol/l at day 0. At day 5 after the procedure was 64.1μmol/l, at day 10 was 45.5μmol/l, and at day 15 was 31.1μmol / l (Table 5 & Figure 5). During the research the index dynamics showed a decrease of direct bilirubin level between the day 15 compared to day 0 (78.1%) in the IG.

The average value of direct bilirubin in patients/CG was 85.9μmol/l at day 0. At day 5 after the procedure was 48.5μmol/l, at day 10 was 37.8μmol/l, and at day 15 was 24.9μmol / l (Table 4 & Figure 4). During the research the index dynamics showed a decrease of direct bilirubin level between the day 15 compared to day 0 (71.0%) in the CG.

The difference between the average values was statistically significant for p< 0.05 (p= 0.033173) in the day 0. The difference at the other days was not statistically significant for p> 0.05 (Table 6).

Table 5 The average values of total and direct bilirubin according evaluation days in both groups

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Figure 5 The average values of total and direct bilirubin according evaluation days in both groups EMBED STATISTICA.Graph \s EMBED STATISTICA.Graph \s

Table 6 Comparison of the total and direct bilirubin values between the patients who underwent UDCA administration (IG) and the patients without UDCA administration (CG)

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The average value of ALT in patients/IG was 174.3U/l at day 0. At day 5 after the procedure was 86.7 U/l, at day 10 was 68.5 U/l, and at day 15 was 56.3 U/l (Table 7 & Figure 7a). During the research the index dynamics showed a decrease of ALT level between the day 15 compared to day 0 (67.7%).

The average value of ALT in patients/CG was 233.3 U/l at day 0. At day 5 after the procedure was 107.8 U/l, at day 10 was 80.1 U/l, and at day 15 was 70.4 U/l (Table 7 & Figure 7a). During the research the index dynamics showed a decrease of ALT level between the day 15 compared to day 0 (69.8%).

The difference between the average values was not statistically significant for p> 0.05 (Table 8).

The average value of AST in patients/IG was 115.9 U/l at day 0. At day 5 after the procedure was 65.3 U/l, at day 10 was 53.0 U/l, and at day 15 was 46.9 U/l (Table 7 & Figure 7a). The index dynamics showed a decrease of AST level between the day 15 compared to day 0 (59.5%).

The average value of AST in patients/CG was 154.5 U/l at day 0. At day 5 after the procedure was 79.5 U/l, at day 10 was 62.7 U/l, and at day 15 was 58.4 U/l (Table 7 & Figure 7a). The index dynamics showed a decrease of AST level between the day 15 compared to day 0 (62.2%).

The difference between the average values was not statistically significant for p> 0.05 (Table 8).

The average value of GGT in patients/IG was 407.8U/l at day 0. At day 5 after the procedure was 228.2 U/l, at day 10 was 172.6 U/l, and at day 15 was 116.3 U/l (Table 7 & Figure 7b). The index dynamics showed a decrease of GGT level between the day 15compared to day 0 (71.5%).

The average value of GGT in patients/CG was 434.4 U/l at day 0. At day 5 after the procedure was 268.2 U/l, at day 10 was 185.9 U/l, and at day 15 was 159.2 U/l (Table 7 & Figure 7b). The index dynamics showed a decrease of GGT level between the day 15 compared to day 0 (63.4%).

The difference between the average values was not statistically significant for p> 0.05 (Table 8).

The average value of ALP in patients/IG was 905.6 U/l at day 0. At day 5 after the procedure was 582.9 U/l, at day 10 was 491.9 U/l, and at day 15 was 461.6 U/l (Table 7 & Figure 7b). The index dynamics showed a decrease of ALP level between the day 15 compared to day 0 (49%).

The average value of ALP in patients/CG was 787.6 U/l at day 0. At day 5 after the procedure was 570.8 U/l, at day 10 was 453.4 U/l, and at day 15 was 387.1 U/l (Table 7 & Figure 7b). The index dynamics showed a decrease of ALP level between the day 15 compared to day 0 (50.8%).

The difference between the average values was not statistically significant for p> 0.05 (Table 8).

Table 7 The average values of ALT, AST, GGT, and ALP according evaluation days in both groups

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Table 8 Comparison of ALT, AST, GGT, and ALP values between the patients who underwent UDCA administration (IG) and the patients without UDCA administration (CG)

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Figure 7a The average values of ALT and AST according evaluation days in both groups EMBED STATISTICA.Graph \s EMBED STATISTICA.Graph \s

Figure 7b The average values of GGT and ALP according evaluation days in both groups EMBED STATISTICA.Graph \s EMBED STATISTICA.Graph \s

The average value of Albumin in patients/IG was 38.4g/l at day 0. At day 5 after the procedure was 38.3g/l, at day 10 was 38.3g/l, and at day 15 was 36.9g/l (Table 9 & Figure 9a). The index dynamics showed a decrease of Albumin level between the day 15 compared to day 0 (3.9%).

The average value of Albumin in patients/CG was 39.0g/l at day 0. At day 5 after the procedure was 41.7g/l, at day 10 was 41.1g/l, and at day 15 was 41.1g/l (Table 9 & Figure 9a). The index dynamics showed an increase of Albumin level between the day 15 compared to day 0 (5.4%).

The difference between the average values was statistically significant for p< 0.05 between albumin in the IG vs albumin in the CG, at the days 5, 10, and 15 after the procedure (p= 0.007722; p= 0.020353; p= 0.002547) (Table 10).

The average value of Creatinine in patients/IG was 83.9 mmol/l at day 0. At day 5 after the procedure was 82.9mmol/l, at day 10 was 85.1mmol/l, and at day 15 was 96.2mmol/l (Table 9 & Figure 9a). The index dynamics showed an increase of Creatinine level between the day 15 compared to day 0 (14.7%). The average value of Creatinine in patients/CG was 83.9 mmol/l at day 0. At day 5 after the procedure was 90.7mmol/l, at day 10 was 94.6mmol/l, and at day 15 was 92.8 mmol/l (Table 9 & Figure 9a). The index dynamics showed an increase of Creatinine level between the day 15 compared to day 0 (13%). The difference between the average values was not statistically significant for p> 0.05 (Table 10).

The average value of Neutrophil/lymphocyte ratio in patients/IG was 4.8 at day 0. At day 5 was 3.1, at day 10 was 3.3, and at day 15 was 3.4 (Table 9 & Figure 9b). The index dynamics showed a decrease of Neutrophil/lymphocyte ratio between the day 15 compared to day 0 (29%).

The average value of Neutrophil/lymphocyte ratio in patients/CG was 3.5 at day 0. At day 5 was 2.9, at day 10 was 2.6, and at day 15 was 2.9 (Table 9 & Figure 9b). The index dynamics showed a decrease of Neutrophil/lymphocyte ratio between the day 15 compared to day 0 (17%).

The difference between the average values was not statistically significant for p> 0.05 (Table 10).

The average value of Urea in patients/IG was 6.2 mmol/l at day 0. At day 5 after the procedure was 5.5 mmol/l, at day 10 was 6.1mmol/l, and at day 15 was 6.7mmol/l (Table 9 & Figure 9b). The index dynamics showed an increase of Urea level between the day 15 compared to day 0 (8.1%). The average value of Urea in patients/CG was 5.3 mmol/l at day 0. At day 5 after the procedure was 5.9mmol/l, at day 10 was 6.1mmol/l, and at day 15 was 6.5mmol/l (Table 9 & Figure 9b). The index dynamics showed an increase of Urea level between the day 15 compared to day 0 (22.6%). The difference between the average values was not statistically significant for p> 0.05 (Table 10).

The average value of Glucose in patients/IG was 6.9mmol/l at day 0. At day 5 after the procedure was 6.6mmol/l, at day 10 was 6.7mmol/l, and at day 15 was 6.8mmol/l (Table 9 & Figure 9b). The index dynamics showed a decrease of Glucose level between the day 15 compared to day 0 (1.4%). The average value of Glucose in patients/CG was 6.4mmol/l at day 0. At day 5 after the procedure was 6.6mmol/l, at day 10 was 6.4mmol/l, and at day 15 was 6.2mmol/l (Table 9 & Figure 9b). The index dynamics showed a decrease of Glucose level between the day 15 compared to day 0 (3.1%). The difference between the average values was not statistically significant for p> 0.05 (Table 10).

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