Gepabene in the treatment of the hepatobiliary system in the elderly

Compound

Material and methods

The study included 33 patients (15 men and 18 women, mean age 54.2 ± 6.8 years) who suffered from GPD. According to the design of the study, before its start (1st visit) and after completion (after 12 weeks of therapy), each patient underwent a comprehensive clinical, laboratory and instrumental examination.

The diagnosis of the disease was based on a thorough analysis of the nature of the complaints (the assessment of the severity of symptoms was carried out in points on a Likert scale), anamnesis data, the results of a physical examination, laboratory tests (general blood and urine tests, biochemical blood tests: bilirubin, glucose, protein, cholesterol, triglycerides, urinary acid, AST, ALT, ALP, GGTP) and instrumental (ultrasound and/or magnetic resonance imaging of the liver) studies (Fig. 1, 2).

The study included persons of both sexes who suffered from GBD, aged from 18 to 60 years.

The study did not include patients with viral or autoimmune hepatitis/LC, the presence of severe concomitant pathology, taking hepatoprotective drugs, and pregnant women.

After the patient was included in the study, Gepabene was prescribed 1 capsule 3 times a day with meals (taken without chewing, with a small amount of water). At intermediate visits after 4 and 8 weeks of treatment, the patient’s complaints and examination results were assessed, paying attention to the presence of side effects. After completion of therapy (after 12 weeks), a re-examination was carried out.

Pharmacodynamics

Gepabene® is a combination preparation of plant origin, containing fumaria extract and milk thistle extract.

Fumarica officinalis extract, containing the alkaloid fumarin, normalizes the amount of secreted bile, relieves spasm of the gallbladder and bile ducts, facilitating the flow of bile into the intestines.

Milk thistle fruit extract contains silymarin, which exhibits a hepatoprotective effect in acute and chronic intoxication, binds free radicals and toxic substances in liver tissue, has antioxidant and membrane-stabilizing activity, stimulates protein synthesis, and promotes the restoration of liver cells.

Gepabene® normalizes liver function in various chronic pathological conditions.

Gepabene in the treatment of the hepatobiliary system in the elderly

Doctor of Medical Sciences L.Yu. Ilchenko

Central Research Institute of Gastroenterology, Moscow

The socio-economic conditions of the last decade of the 20th century led to a sharp change in the demographic situation in Russia. Its hallmark has been the rise of the elderly as the fastest growing population group. According to the WHO classification, the elderly group consists of people aged 60–74 years. The share of elderly people in the Russian Federation reaches 16%, and further “aging” of the country’s population is expected in the near future. In this regard, the relevance of research devoted to various areas of geriatrics increases significantly.

Currently, the problem of liver and biliary system lesions in elderly people remains poorly understood.

It is known that the liver is a relatively slowly aging organ, which is not characterized by the development of specific age-related diseases. However, a slowdown in metabolic processes and the functioning of the alcohol dehydrogenase system, the presence of cyclical shifts in hormonal activity, a decrease in protein, carbohydrate and lipid metabolism, as well as a decrease in size and blood flow lead to morphological and functional changes in the human liver, starting from the age of 50 [2]. Along with this, a decrease in physical activity, an unbalanced diet, alcohol abuse, obesity, diabetes mellitus, taking a large number of medications, and chronic heart failure contribute to the development of pathology of the hepatobiliary system.

Among non-viral liver diseases in the elderly, fatty hepatosis, non-alcoholic steatohepatitis and its resulting cirrhosis, as well as drug- and alcohol-induced liver damage should be highlighted [4]. Risk factors leading to the development of hepatic steatosis include chronic alcohol intoxication, diabetes mellitus, obesity, nutritional protein deficiency, strict vegetarianism, systematic use of certain medications (some antibiotics, hormonal drugs, non-steroidal anti-inflammatory drugs, etc.), toxic substances and genetic predisposition. Careful collection of anamnesis in elderly and senile patients allows us to establish the presence, as a rule, of several possible causes for the development of fatty infiltration. On the one hand, steatosis is the result of excessive intake of free fatty acids into the liver, a decrease in the rate of b-oxidation in the mitochondria of liver cells, increased formation and absorption by enterocytes, and on the other hand, liver damage, which disrupts the synthesis of lipoproteins. With a combination of fatty and lymphoid cell infiltration or necrosis of hepatocytes, steatohepatitis develops. The formation of “false” microlobules indicates the development of liver cirrhosis in patients in this group.

Taking into account the presence of many diseases (multimorbidity) characteristic of older people, the assessment of status should take into account the clinical manifestations of concomitant pathology and its contribution to the development of liver damage. Liver changes in cardiovascular pathology in people over 60 years of age deserve special attention. In this case, both minor structural changes and far-reaching ones can be detected, leading to the formation of cardiac cirrhosis. In the pathogenesis of these conditions, atherosclerotic processes in the mesenteric arteries, leading to a decrease in portal blood flow, hypoxia, inhibition of the enzymatic activity of cytochrome P450, etc., can play a significant role.

Along with this, in elderly people there are disturbances in the excretory function of the liver. In chronic liver diseases of toxic, alcoholic and drug etiology, the development of hepatocyte necrosis, as well as impaired transport function (due to blockade of membrane and intracellular transport proteins) can lead to changes in the process of bile secretion.

In addition, an increase in cholesterol content with a decrease in the production of bile acids and organic anions entails an increase in the lithogenicity of bile and a decrease in its concentration ability, and in the presence of a violation of the contractile function of the gallbladder (contractile function decreases with age), the formation of sludge (clot), which can contribute to development of cholelithiasis [5,6,8]. The mucous membrane of the gallbladder secretes a hormone that inhibits cholecystokinin, which is involved in the regulation of bile formation. Deficiency of the latter, the presence of lithogenic bile, as well as the absorption of its components by the mucous membrane of the gallbladder lead to the development of cholesterosis.

It has been shown that in case of dyslipoproteinemia (disorders of lipid metabolism), often found in elderly people, often suffering from various manifestations of atherosclerosis, including chronic abdominal ischemia or the presence of fatty hepatosis, biliary pancreatitis, the earliest clinical signs of lipid distress syndrome are cholesterosis of the gallbladder with impaired its motor-evacuation function. At the same time, signs of a violation of the outflow of bile in the liver and a slowdown in its flow into the intestines are revealed.

There is a direct connection between the development of cholelithiasis and lipid metabolism disorders, and liver steatosis is often combined with gallbladder dysfunction, especially in the presence of cholelithiasis [3,7].

It has been established that in elderly and senile people, stones in the gallbladder are detected in almost 70% of cases. Often, as a result of cholecystectomy, pathological conditions of the digestive system develop. Three variants of these abnormalities have been identified: postcholecystectomy syndrome (dysfunction of the sphincter of Oddi), as well as biliary hypertension with the presence of organic obstacles to the flow of bile (choledocholithiasis, stenosis and insufficiency of the major duodenal papilla, stricture of the bile ducts, failure of bile-ducting anastomoses); development or increase in clinical manifestations of concomitant diseases, namely: chronic pancreatitis, gastric or duodenal ulcer, duodenitis, hiatal hernia, dyskinesia of the large or small intestine. The symptom complex of these diseases can either initially accompany cholelithiasis or develop immediately after cholecystectomy. It has been established that after cholecystectomy, 70-80% of patients have insufficiency of the sphincter of Oddi with continuous flow of bile into the lumen of the duodenum, and hypertonicity is less common.

Severe hypotension of the gallbladder and sphincter of Oddi persists for a long time even after gastric surgery. In addition, during gastric resection, secretory and motor-evacuation disorders may develop due to a decrease in the production of hormones, including cholecystokinin-pancreozymine.

A significant role in the formation of biliary disorders belongs to psycho-emotional overload and stressful situations. In old age, despite an increase in the number of somatic diseases and a decrease in income, the risk of alcohol abuse increases, which, in turn, contributes to the development of depression in 15% of patients. Dysfunction of the gallbladder and sphincter of Oddi can be a manifestation of general neurosis, the cause of which is loss of a job or finding a new one, loss of loved ones, loneliness, etc.

The influence of psychogenic factors on the biliary system is realized through the cortical and subcortical formations of the central nervous system, as well as the endocrine system. Violation of the production of digestive hormones and neuropeptides, insufficient formation of thyroidin, oxytocin, corticosteroid and sex hormones leads to changes in the tone of the gallbladder and sphincters of the biliary system.

Until now, there is practically no data on epidemiology, clinical symptoms, treatment of elderly and senile patients suffering from chronic liver diseases with concomitant biliary pathology.

All of the above, especially taking into account the mandatory use of several drugs by elderly patients, dictates the need to create new drugs. Among the drugs that improve the functional state of the liver and biliary system, Gepabene (ratiopharm), a new combination drug of plant origin, has been successfully used in gastroenterology in recent years [4].

Gepabene contains milk thistle and fumaria officinalis. Milk thistle fruit extract contains the well-known hepatoprotector silymarin, a group of flavonoid compounds. The complex of its isomers (silibinin, silydianin and silicristin) has hepatoprotective, membrane-stabilizing, antioxidant, antifibrotic, immunomodulatory and antitoxic effects. Alkaloid fumarin is a remedy that normalizes both weakened and increased choleresis, has an antispasmodic effect, eliminates spasm of the sphincter of Oddi, prevents the development of stones in the ductal system, regulates bile secretion processes, facilitating the flow of bile into the intestines. In addition, through a feedback mechanism, it reduces the absorption of cholesterol in the intestine, the secretion of cholesterol into bile and the synthesis of cholesterol in the liver, which reduces the lithogenicity of bile.

The purpose of our study was to study the effectiveness of Gepabene for the pathology of the hepatobiliary system in elderly patients.

Materials and methods

In the department of chronic liver diseases of the Central Research Institute of Gastroenterology in 2002, 849 patients with predominantly chronic liver diseases of various etiologies were examined and treated. To exclude the viral etiology of liver damage, markers of hepatitis B, C, G and TT were determined using enzyme immunoassay and polymerase chain reaction. Among those examined, 42 patients (13 men and 29 women) aged from 60 to 74 years (average age 64.9) with chronic liver damage of non-viral etiology (alcohol, drug, metabolic) were selected. This group of patients was examined according to a specific plan, which included an analysis of complaints , anamnesis, objective status. We assessed the main clinical syndromes, as well as the results of laboratory tests (alanine (AlAT) and aspartic (AST) aminotransferases, bilirubin, alkaline phosphatase (ALP), g-glutamyl transpeptidase (GGTP), amylase, lipase, glucose) . Lipids (total cholesterol, triglycerides, high- and low-density lipoproteins) in the blood serum were determined by the spectrophotometric enzyme method, and the concentration of total bile acids using gas-liquid chromatography. Ultrasound examination was carried out according to the standard method, on an empty stomach. The volume of the gallbladder and its contractile function were determined with using a choleretic breakfast (100 ml of 10% cream) and studying the ejection fraction after 40 minutes. and 1 hour. The motor evacuation function of the gallbladder was assessed as normal if its volume by 30-40 min. decreased to 1/31/2 from the original. A morphological study of liver tissue was carried out in 12 elderly patients. Gepabene was prescribed in a dose of 2 capsules 3 times a day. The criteria for the effectiveness of Gepabene therapy were the dynamics of the above tests initially and 1 month after therapy.

Research results

Pain syndrome in the form of aching sensations and/or heaviness in the right hypochondrium was noted by 82% of patients; dyspeptic syndrome, characterized by the presence of dryness and often bitterness in the oral cavity, nausea, loss of appetite, sometimes heartburn, flatulence, and a tendency to constipation 78%; asthenovegetative syndrome with a predominance of weakness and fatigue, sleep disturbances in 18% of those examined.

During examination, jaundice of the sclera was detected in 13 patients; liver enlargement was found in the majority of those examined. At the same time, the size of the spleen was increased in isolated cases. “Minor” liver signs were found in only 9 patients. Half of the patients suffered from stage III obesity, and 68% of the entire group of patients had type 2 diabetes mellitus, associated with dyslipidemia and hypothyroidism. In 86% of elderly patients, a biochemical blood test revealed moderate hyperenzymemia (23 norms of ALT and 2.5-3.5 norms of AST), in 42% of cases increased activity of GGTP and alkaline phosphatase. During a morphological study, 8 out of 12 patients were found to have large-droplet fatty infiltration, less often (2) small-droplet fatty degeneration or its mixed form was detected (2), in some cases (6) polymorphocellular intralobular infiltration. Various degrees of fibrosis severity were noted, from perisinusoidal to signs of cirrhosis in 4 patients. As a result of the examination, 18 elderly patients were diagnosed with liver steatosis, 6 with non-alcoholic steatohepatitis, 14 with chronic hepatitis of alcoholic etiology, and in 4 cases with the formation of liver cirrhosis.

To assess the condition of the biliary system, all patients underwent ultrasonography with examination of motor-evacuation function. In 35 subjects, changes in the gallbladder were detected (3 stones, 20 suspension, 4 kinks in the area of ​​the bladder body, 8 cholesterosis). In 3 elderly patients, the gallbladder was absent (history of cholecystectomy for cholelithiasis); in 4 cases, no changes were detected. Inhomogeneous contents of the gallbladder, which manifested itself in the form of pinpoint inclusions of increased density, without clear contours, suspended or in the form of sediment and not giving an ultrasonic shadow, i.e. "sludge" was considered as a "pre-stone" stage. A study of the motor-evacuation function of the gallbladder revealed a predominance of hypotension (in 32 cases). An increase in total bile acids in the peripheral blood was noted in elderly patients with alcoholic liver damage occurring with cholestasis syndrome. Moreover, in all cases, these patients showed signs of biliary insufficiency.

Thus, the presented set of examinations, carried out in elderly patients with chronic liver diseases of non-viral etiology, made it possible to identify a high frequency of biliary tract dysfunctions, as well as their combination with metabolic diseases of the gallbladder.

The basic principle of correcting biliary tract disorders in elderly patients with chronic liver diseases was: prescribing a diet rich in protein, containing short and medium chain triglycerides, choleretic drugs, agents that normalize the motility of the gallbladder and sphincter of Oddi, and fat-soluble vitamins. It was recommended to eat frequently at regular intervals throughout the day to prevent thickening of bile and avoid fried, fatty foods that provoke pain. The inclusion of the drug Gepabene, which has a dual effect, in the therapeutic complex led to a clinical improvement in the course of the disease, which was characterized by a decrease in pain, as well as a reduction in dyspeptic and asthenic manifestations.

A positive effect was noted in 88% of patients. While taking Gepabene, the quality of life was rated as good by 62% of elderly patients, satisfactory by 26%, unchanged by 12%. Among the patients with no improvement were patients with cholelithiasis. During dynamic observation, attacks of pain in the right hypochondrium with irradiation to the scapula were recorded, and a transient increase in the activity of AST, ALP and GGTP was noted by 1.5-2 times compared to the initial level, which did not exclude the presence of dysfunction of the sphincter of Oddi (biliary variant ). Two patients underwent elective laparoscopic cholecystectomy. In one of the three who had previously undergone surgery, pain in the left hypochondrium in the absence of symptoms of pancreatitis was combined with hyperlipasemia, which suggested a pancreatic variant of sphincter of Oddi dysfunction.

Dynamics of changes in qualitative and quantitative tests under the influence of Gepabene in elderly patients with pathology of the hepatobiliary system:

• a decrease in pain was noted on days 3-4 from the start of taking the drug and its disappearance by the end of the second week in 58% of patients; improvement in appetite and normalization of stool by the end of the first week of therapy in 82%; improved mood and decreased weakness after 3 weeks in 64%;
• cytolysis indicators were normalized in 24%, a tendency towards normalization of hyperenzymeemia (up to 1.3 times the norm) was detected in 53% of cases;
• a decrease in cholestasis enzymes to 1.5 norms was obtained in all cases of increase;
• a 28% decrease in total cholesterol and triglycerides was detected in patients with concomitant diabetes mellitus;
• normalization of the contractile function of the gallbladder was noted in 64% who initially had hypomotor type dysfunction; an increase in choleretic activity was found in 31% of cases;
• disappearance of “sludge” was observed in 28% of patients.

During the course of Gepabene therapy, the size of the liver and spleen according to physical and ultrasound examinations did not change. Also, no statistically significant changes in the concentration of total bile acids in the blood serum were obtained, which may indicate a violation of their transport in hepatocytes.

Conclusion

Thus, the herbal preparation Gepabene can be recommended for the treatment of biliary dysfunctions in elderly patients as a choleretic, antispasmodic and hepatoprotective agent.

The use of Gepabene leads to a decrease in clinical biochemical activity in elderly patients with chronic liver damage of alcoholic etiology and metabolic changes.

Gepabene eliminates disturbances in the motor-evacuation function of the biliary tract: an increase in choleresis and an improvement in the contractile function of the gallbladder are noted. Can be used as an effective remedy in the treatment of cholelithiasis (pre-stone stage).

The drug was well tolerated, no adverse reactions were noted.

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Published with permission from the administration of the Russian Medical Journal.