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Drug-induced gallbladder disease. Incidence, aetiology and management
Abstract
A great variety of drugs is reported to induce gallbladder disease by various pathogenetic mechanisms. Early epidemiological studies indicated a doubled risk of gallbladder disease in women taking oral contraceptives. More recent studies, however, have failed to confirm those findings; these conflicting results might be explained by the different methods used to define gallbladder disease. It was shown that the lithogenic index of the bile is increased during intake of oral contraceptives. Estrogens cause hypersecretion of cholesterol in bile, due to increase in lipoprotein uptake by the hepatocyte. Progesterone inhibits acyl coenzyme A-cholesterol acyl transferase (ACAT) activity, causing delayed conversion of cholesterol to cholesterol esters. Of the lipid lowering drugs, only clofibrate has been shown to increase the risk for gallstone formation. The other fibric acid derivatives have similar properties, but clinical experience is not as extensive. They seem to be inhibitors of the ACAT enzyme system, thereby rendering bile more lithogenic. Conflicting epidemiological data exist regarding the induction of acute cholecystitis by thiazide diuretics. Ceftriaxone, a third-generation cephalosporin, is reported to induce biliary sludge in 25 to 45% of patients, an effect which is reversible after discontinuing the drug. The sludge is occasionally a clinical problem. It was clearly demonstrated that this sludge is caused by precipitation of the calcium salt of ceftriaxone excreted in the bile. Long term use of octreotide is complicated by gallstone formation in approximately 50% of patients after 1 year of therapy, due to gallbladder stasis. Hepatic artery infusion chemotherapy by implanted pump is shown to be associated with a very high risk of chemically induced cholecystitis. Prophylactic cholecystectomy at the time of pump implantation is therefore advocated. Some drugs, such as erythromcyin or ampicillin, are reported to cause hypersensitivity-induced cholecystitis. Furthermore, there are reports on the influence of cyclosporin, dapsone, anticoagulant treatment, and narcotic and anticholinergic medication in causing gallbladder disease.
... There is no direct relationship between toxicity seen within the liver and that occurring in the gallbladder, and modes of action affecting gall bladder toxicity are not generally applicable to hepatic toxicity and vice versa. 47 It is recommended that the 2 organs be handled as separate in similarity between the liver and the pancreas, with regard to their aggregate exposure to chemically induced toxicity. Primary effects on the biliary system that result in blockage of bile outflow, can secondarily affect the liver most commonly as inflammation which can be seen in the periportal regions of the lobules. ...
... The chemical induction of these lesions is however fairly rare and most of the biliary changes seen in the liver are unrelated to primary changes in the biliary system. 47,48 The rationale for arranging the various hepatic pathologies into primary or secondary events is summarized in Table 2. ...
... There are a limited number of chemicals that can induce necrosis of the mucosa of the biliary system as a primary effect, which is often accompanied by hepatocellular degeneration and inflammation, but which occurs prior to the hepatic damage. 47,50,51 The industrial chemical intermediate, dibutyltin dichloride, has been used as a model for the induction of acute pancreatitis in laboratory rodents, but which also induces a primary biliary mucosal necrosis of the common bile duct and larger interlobular ducts of the liver. [52][53][54][55] The necrosis of the epithelial cells is followed by a series of secondary pathological changes such as submucosal edema, extrahepatic cholestasis, and inflammation both within the affected tissues and throughout the periportal regions of the liver lobules. ...
The increased concern on the consequence of exposure to multiple chemical combinations has led national regulatory authorities to develop different concepts to conduct risk assessments on chemical mixtures. Pesticide residues were identified as “problem formulation” in the respective European regulations and in this context, the European Food and Safety Authority has suggested to group pesticidal active ingredients (AIs) into cumulative assessment groups (CAGs) based on the toxicological properties of each AI. One proposed CAG, on the liver, currently consists of 15 subgroups, each representing a specific hepatotoxic effect observed in toxicity studies. Dietary cumulative risk assessments would then have to be conducted assuming dose additivity of all members of each CAG subgroup.
The purpose of this publication is to group AIs based upon the knowledge of the pathogenesis of liver effects to discriminate between primary end points (direct consequence of chemical interaction with a biological target) and secondary end points (which are a consequence of, or that arise out of, a previous pathological change). Focusing on the relevant primary end points strengthens and simplifies the selection of compounds for cumulative risk assessment regarding the liver and better rationalizes the basis for chemical grouping. Relevant dose additivity is to be expected at the level of the primary/leading pathological end points and not at the level of the secondary end points. We recognize, however, that special consideration is needed for substances provoking neoplasia, and this category is included in the group of primary end points for which chemicals inducing them are grouped for risk assessment.
Using the pathological basis for defining the respective CAGs, 6 liver subgroups and 2 gallbladder/bile duct groups are proposed. This approach simplifies the cumulative assessment calculation without obviously affecting consumer safety.
... К числу медикаментов, способствующих появлению билиарного сладжа, относятся циклоспорин, цефтриаксон (роцефин) и ряд других. Следует отметить, что 40% цефтриаксона выделяется с желчью, образуя нерастворимую кальциевую соль, сладж выявляют у 25-45% пациентов, но чаще всего он исчезает после отмены препарата [16]. Октреотид (сандостатин) ингибирует выброс холецистокинина, способствует стазу желчного пузыря, увеличивает продукцию гидрофобной дезоксихолевой кислоты -билиарный сладж образуется у 50% больных в течение первого года применения данного средства [9,16]. ...
... Следует отметить, что 40% цефтриаксона выделяется с желчью, образуя нерастворимую кальциевую соль, сладж выявляют у 25-45% пациентов, но чаще всего он исчезает после отмены препарата [16]. Октреотид (сандостатин) ингибирует выброс холецистокинина, способствует стазу желчного пузыря, увеличивает продукцию гидрофобной дезоксихолевой кислоты -билиарный сладж образуется у 50% больных в течение первого года применения данного средства [9,16]. Препараты кальция при лечении остеопороза способствуют образованию билирубинового билиарного сладжа; клофибрат подавляет секрецию желчных кислот; при длительном приеме морфина (например, при наркомании) за счет спазма сфинктера Одди также развивается билиарный сладж [16]. ...
... Октреотид (сандостатин) ингибирует выброс холецистокинина, способствует стазу желчного пузыря, увеличивает продукцию гидрофобной дезоксихолевой кислоты -билиарный сладж образуется у 50% больных в течение первого года применения данного средства [9,16]. Препараты кальция при лечении остеопороза способствуют образованию билирубинового билиарного сладжа; клофибрат подавляет секрецию желчных кислот; при длительном приеме морфина (например, при наркомании) за счет спазма сфинктера Одди также развивается билиарный сладж [16]. ...
1,7-4%, среди лиц с гастроэнтерологическими жалобами-7,5%. В числе патогенетических механизмов били-арного сладжа выделяют: снижение синтеза желчных кислот, нарушение нейрогуморальной синхрониза-ции сократительной функции желчного пузыря, при-водящее к его гипотонии, изменение качественного состава пронуклеаторов билиарного сладжа, в част-ности гликозамингликанов, ускоряющее процесс слияния везикул в желчи, что в целом способствует повышению ее литогенности. Существует несколько классификаций этого заболевания, основанных на этиологии, сонографической картине и химическом составе сладжа. Основными факторами риска при-знают желчнокаменную болезнь, сахарный диабет, холестаз различного генеза, беременность, прием некоторых медикаментов (цефтриаксон, октреотид, клофибрат, препараты кальция и т. д.), серповид-но-клеточную анемию и др. Течение билиарного сладжа может быть бессимптомным, с признаками билиарной диспепсии или с осложнениями, такими, как панкреатит, стенозирующий папиллит, острый холангит и др. Наиболее эффективным средством терапии является урсодезоксихолевая кислота, в случае сочетания билиарного сладжа с нефункцио-нирующим желчным пузырем показано хирургиче-ское вмешательство. Заключение. Пациенты гастроэнтерологиче-ского профиля, а также лица с факторами риска билиарного сладжа должны быть обследованы с целью выявления данной патологии, своевременно-го назначения курса лечения и ранней профилакти-ки осложнений. Ключевые слова: билиарный сладж, литоген-ность желчи, патогенез, урсодезоксихолевая кисло-та. Biliary sludge I.N. Grigor'yeva The aim of review. To describe prevalence, basic mechanisms, risk factors and variants of course of bili-ary sludge, and methods of its treatment. Original standpoints. Biliary sludge consists of inhomogeneous structures, suspension and clots in bile. Its prevalence in general population ranges 1,7 to 4%, and is 7,5% of patients with gastroenterological complaints. Pathogenic mechanisms of biliary sludge include following: decrease of bile acids synthesis, disorders of neurohumoral synchronization of gall-bladder contractility, resulting in its hypotony, qualitative changes of pronucleator composition of biliary sludge, in particular-glycosaminoglycans, accelerating process of vesicles coalescence in bile, that in general promotes increase of its lithogenicity. There are some classifications of this disease based on etiol-ogy, sonographic pattern and chemical composition of sludge. Cholelithiasis, diabetes mellitus, cholestasis of a various origin, pregnancy, intake of some medicines (ceftriaxone, octreotide, clofibrate, calcium-containing agents, etc.), sickle-cell anemia, etc. are known as major risk factors. Course of biliary sludge can be asymptomatic, with signs of biliary dyspepsia or with complications including pancreatitis, constrictive papil-litis, acute cholangitis, etc. The most effective treatment agent is ursodeoxycholic acid, if of biliary sludge is combined to nonfunctioning gallbladder surgical intervention is indicated. Conclusion. Gastroenterological patients, and patients with risk factors of biliary sludge should undergo investigation for revealing this disease, well-timed prescription treatment and early prophylaxis of complications .
... [87,88] ACC and drugs: Drugs promoting the formation of stones are indirectly associated with a risk of ACC. [89] It is reported that women taking oral conceptives have a higher risk of having gallbladder disease. [90] Fibrate used for the treatment of hyperlipidemia is shown to be associated with gallstone diseases. ...
... [92] The administration of a large dose of ceftriaxone, a third-generation cephalosporin antimicrobial, in infants, precipitates calcium salt in bile and forms a sludge in 25%-45% of them, but these effects disappear when the medication is discontinued. [89] It is reported that the long-term administration of octreotide causes cholestasis, and that administration for a year causes cholelithiasis in 50% of patients. [89] ACC and Ascaris: Complications in the biliary tract include cholelithiasis with the ascarid as a nidus for stone formation and ACC. ...
... [89] It is reported that the long-term administration of octreotide causes cholestasis, and that administration for a year causes cholelithiasis in 50% of patients. [89] ACC and Ascaris: Complications in the biliary tract include cholelithiasis with the ascarid as a nidus for stone formation and ACC. [93] Biliary tract disease is caused by the obstruction of the hepatic and biliary tracts by the entry of ascarids from the duodenum through the papilla. ...
Acute cholecystitis is the inflammation of the gall bladder. The most common cause is the presence of gall stones. It accounts for 3% to 10% of all patients with acute abdominal pain, being higher in patients >50 years than in younger patients. More than 80% of patients with cholelithiasis are unaware of their disease and are asymptomatic. Therefore less than 20% of these patients become symptomatic with attacks of biliary colic. Only 20% of these symptomatic patients develop ACC.
... According to the review by Michielsen et al.,53 regarding the association between drugs and acute cholecystitis, 90%–95% of acute cholecystitis cases are caused by cholelithiasis, and drugs promoting the formation of stones are indirectly associated with a risk of acute cholecystitis (level 4). The etiological mechanism of drug-associated gallbladder diseases, as discussed in the review,53 is shown in Table 7. ...
... Drugs as etiologic agents. According to the review by Michielsen et al.,53 regarding the association between drugs and acute cholecystitis, 90%–95% of acute cholecystitis cases are caused by cholelithiasis, and drugs promoting the formation of stones are indirectly associated with a risk of acute cholecystitis (level 4). The etiological mechanism of drug-associated gallbladder diseases, as discussed in the review,53 is shown in Table 7. ...
... One report suggests that thiazides induce acute cholecystitis (level 3b),56 and another report denies this association (level 3b).57 The administration of a large dose of ceftriaxone, a third-generation cephalosporin antimicrobial, in infants, precipitates calcium salt in bile and forms a sludge in 25%–45% of them, but these effects disappear when the medication is discontinued (level 4).53 It is reported that the longterm administration of octreotide causes cholestasis, and that administration for a year causes cholelithiasis in 50% of patients (level 4).53 Hepatic artery infusion will cause chemical cholecystitis (level 4).53 Erythromycin and ampicillin are reported to be a cause of hypersensitive cholecystitis (level 4).53 ...
This article discusses the definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis. Acute cholangitis and cholecystitis mostly originate from stones in the bile ducts and gallbladder. Acute cholecystitis also has other causes, such as ischemia; chemicals that enter biliary secretions; motility disorders associated with drugs; infections with microorganisms, protozoa, and parasites; collagen disease; and allergic reactions. Acute acalculous cholecystitis is associated with a recent operation, trauma, burns, multisystem organ failure, and parenteral nutrition. Factors associated with the onset of cholelithiasis include obesity, age, and drugs such as oral contraceptives. The reported mortality of less than 10% for acute cholecystitis gives an impression that it is not a fatal disease, except for the elderly and/or patients with acalculous disease. However, there are reports of high mortality for cholangitis, although the mortality differs greatly depending on the year of the report and the severity of the disease. Even reports published in and after the 1980s indicate high mortality, ranging from 10% to 30% in the patients, with multiorgan failure as a major cause of death. Because many of the reports on acute cholecystitis and cholangitis use different standards, comparisons are difficult. Variations in treatment and risk factors influencing the mortality rates indicate the necessity for standardized diagnostic, treatment, and severity assessment criteria.
... According to a review by Michielsen et al., drugs promoting the generation of gallbladder stones were indirectly associated with a risk of acute cholecystitis [62]. A developmental mechanism of drug-associated gallbladder diseases in that review is presented in Table 4. Statins, which are drugs for hyperlipidemia, may decrease the risk for cholecystectomy due to gallbladder stones [63][64][65][66]. ...
... There are also reports suggesting that thiazide was involved in the increased risk for cholecystectomy due to acute cholecystitis/gallbladder diseases [67][68][69], although there is a report that failed to detect an association [70]. Transcatheter hepatic arterial chemotherapy has been indicated to potentially induce chemical cholecystitis due to direct toxicity [62,71]. The relative risk for the onset of cholecystitis or cholecystectomy due to hormone replacement therapy was two-fold larger [72,73]. ...
While referring to the evidence adopted in the Tokyo Guidelines 2007 (TG07) as well as subsequently obtained evidence, further discussion took place on terminology, etiology, and epidemiological data. In particular, new findings have accumulated on the occurrence of symptoms in patients with gallstones, frequency of severe cholecystitis and cholangitis, onset of cholecystitis and cholangitis after endoscopic retrograde cholangiopancreatography and medications, mortality rate, and recurrence rate. The primary etiology of acute cholangitis/cholecystitis is the presence of stones. Next to stones, the most significant etiology of acute cholangitis is benign/malignant stenosis of the biliary tract. On the other hand, there is another type of acute cholecystitis, acute acalculous cholecystitis, in which stones are not involved as causative factors. Risk factors for acute acalculous cholecystitis include surgery, trauma, burn, and parenteral nutrition. After 2000, the mortality rate of acute cholangitis has been about 10 %, while that of acute cholecystitis has generally been less than 1 %. After the publication of TG07, diagnostic criteria and severity assessment criteria were standardized, and the distribution of cases according to severity and comparison of clinical data among target populations have become more subjective. The concept of healthcare-associated infections is important in the current treatment of infection. The treatment of acute cholangitis and cholecystitis substantially differs from that of community-acquired infections. Cholangitis and cholecystitis as healthcare-associated infections are clearly described in the updated Tokyo Guidelines (TG13).Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html .
... We diagnosed the patients with acalculous cholecystitis based on the findings from the physical examination, such as tenderness in the right hypochondrium; the laboratory data, such as an increase in the WBC count and elevation of CRP levels; and the imaging findings, such as wall thickening and debris in the gallbladder. A number of drugs have been reported to induce gallbladder diseases, including hypersensitivity-induced cholecystitis (13). Most cases of acute cholecystitis are caused by gallstones, but an allergic reaction has also been reported to be involved in some cases (14). ...
A 70-year-old woman with chronic hepatitis C was admitted to our hospital due to liver injury, cholecystitis, and disseminated intravascular coagulation with a fever and skin rash. She had been on a combination regimen of daclatasvir and asunaprevir for 2 weeks of a 24-week regimen. Because of the symptoms, laboratory findings, results of a drug-induced lymphocyte stimulation test, and pathological findings of liver biopsy, we diagnosed her with drug-induced liver injury. Although daclatasvir and asunaprevir combination therapy is generally well-tolerated, some serious adverse effects have been reported. Our findings indicate that immunoallergic mechanisms were associated with daclatasvir and asunaprevir-induced liver injury.
... Otras entidades se han asociado a la formación de cálculos biliares, tales como el uso de los siguientes medicamentos: fibratos [19], tiacidas [20], ceftriaxona en niños [21], ocreótido por largos periodos [22] y la terapia de remplazo hormonal. Con menor frecuencia, las neoplasias, los parásitos y los pólipos son etiología de la obstrucción prolongada del drenaje de la vesícula biliar, bien sea en su cuello o el conducto cístico, al favorecer la formación de cálculos biliares. ...
Resumen La colecistitis calculosa aguda es la causa más importante de colecistectomías en el mundo. En esta revisión de tema se resume la fisiopatología del proceso inflamatorio de la vesícula biliar secundaria a la obstrucción de la vía biliar, así como sus manifestaciones clínicas, estudios diagnósticos y su manejo médico-quirúrgico. Palabras clave: enfermedades de la vesícula biliar, colecistitis aguda, colecistectomía. Title Acute calculous cholecystitis Abstract Acute calculous cholecystitis is the most important cause of cholecystectomies worldwide. We review the physiopathology of the inflammatory process in this organ secondary to biliary tract obstruction, as well as its clinical manifestations, workup, and the treatment it requires.
... Drugs such as erythromycin or ampicillin are reported to cause hypersensitivity-induced cholecystitis. Furthermore, there are reports on the effects of cyclosporin, dapsone, anti-platelet drugs, and narcotic and anticholinergic medication on the development of gallbladder disease (10). Conflicting epidemiological data exist regarding the induction of acute cholecystitis by thiazide diuretics. ...
To prospectively evaluate the incidence of biliary sludge and pseudolithiasis in children treated with ceftriaxone.
Thirty-three children (14 girls, 19 boys) treated with ceftriaxone for prophylaxis (n=13) or for an infection (n=20) were included in this study. The incidences of biliary sludge and pseudolithiasis were investigated using ultrasonography. The ultrasonographic evaluations were performed prior to and on the 4th-5th days and on the 8th-10th days of treatment. The patients who had biliary sludge or pseudolithiasis were followed up with ultrasonographic evaluation periodically until these pathological phenomena disappeared.
Ceftriaxone was administrated intravenously at a dosage of 100 mg kg(-1) day(-1). Serial gallbladder sonograms were performed before treatment and on the 4th-5th and 8th-10th days of therapy. Nineteen children developed pseudolithiasis and sludge in the gallbladder, and all were asymptomatic. No significant differences were found between the patients with normal versus abnormal sonographic findings in regard to gender, age, duration of the therapy, oral restriction except the presence of surgery (P< 0.005).
The combination of oral restriction and surgical procedures may be a causal factor in ceftriaxone-associated biliary pseudolithiasis. It is emphasized that when gallstone and/or sludge are detected in the gallbladder in children by ultrasonographic examination, the administration of ceftriaxone must be sought beyond other causative factors.
... The kidneys eliminate approximately 33-67% of ceftriaxone, and the remainder is eliminated via the biliary system [4]. Ceftriaxone may bind calcium and form insoluble precipitates leading to biliary pseudolithiasis and nephrolithiasis [11][12][13]. In our study, renal stones were seen on ultrasound examination as echogenic foci with posterior shadows. ...
Urinary tract calculi have been reported to account for between 1 in 1,000 and 1 in 7,600 hospital admissions in children in the USA. The annual incidence of urolithiasis in patients older than 10 years is 109 per 100,000 of the population in men and 36 per 100,000 of the population in women in Minnesota. The use of various medications is considered to be one of the etiologic factors of nephrolithiasis. Ceftriaxone is a widely used third-generation cephalosporin that is generally considered very safe, but complications such as biliary pseudolithiasis, and rarely, nephrolithiasis have been reported in children. There is limited information about urolithiasis as a side effect of ceftriaxone. The aim of this study was evaluation of the incidence of nephrolithiasis following ceftriaxone therapy in children. This quasi-experimental before and after study was conducted in Mofid Children's Hospital between 2003 and 2005. All patients were treated with 75 mg/kg intravenous ceftriaxone. Diagnosis of pyelonephritis was based on standard criteria. The first renal ultrasonography was performed on the first or second day of admission and was repeated on the last day of treatment. We also evaluated complicated patients for the third time with renal ultrasonography 3 months after treatment. Stone-forming patients underwent metabolic kidney stone risk factor evaluation. We evaluated 284 patients with pyelonephritis, 185 girls and 99 boys. The first ultrasonography was normal in all of our patients. On the second ultrasonography renal stones were reported in 4 out of 284 cases (1.4% and CI=0.96-1.83%). Underlying metabolic risk factors could not be identified in stone-forming patients. Follow-up ultrasonography 3 months later was normal. The results of our study suggest that ceftriaxone-treated patients may be at an increased risk of kidney stone formation. Stones passed spontaneously in all affected patients so the use of this effective drug can be safely continued. Close monitoring of ceftriaxone-treated patients with regard to kidney stone formation is recommended.
To identify the risk factors and clinical results for acute cholecystitis after covered self-expandable metal stent （SEMS） placement for distal malignant biliary obstruction （MBO）, we have retrospectively examined the clinical outcomes in patients with acute cholecystitis after endoscopic biliary SEMS placement for distal MBO. This was a retrospective study. Between January 2014 and June 2017, 90 patients who were identified to have underwent endoscopic covered SEMS placement for distal MBO at our institution were included in this analysis. Patients with benign biliary strictures after cholecystectomy were excluded. After covered SEMS placement, we followed up with physical examination and laboratory data and continued with the follow-up for as long as possible. The risk factors for acute cholecystitis after covered SEMS placement were then evaluated. Acute cholecystitis was observed in 15 patients （17％） after covered SEMS placement. The median time to the onset of acute cholecystitis after covered SEMS placement was 19 days （interquartile range, 5-127 days）. Cholecystitis was initially treated with percutaneous gallbladder aspiration （PTGBA） in 11 patients, percutaneous gallbladder drainage （PTGBD） in 2 patients, and antimicrobial therapy alone in 2 patients. Five patients （including four patients treated with PTGBA and one patient treated with antimicrobial therapy alone） had cholecystitis recurrence. In a multivariate analysis of the risk factors for cholecystitis after covered SEMS placement, bile duct cancer （odds ratio （OR）, 12; P＝0.028）, thin bile duct diameter （≤8mm） （OR, 5.2; P＝0.048）, and chemotherapy （OR, 12.6; P＝0.008） were identified as the significant risk factors. Bile duct cancer, thin bile duct diameter, and chemotherapy were identified as risk factors for acute cholecystitis after endoscopic covered SEMS placement for distal MBO. PTGBA is useful as the initial treatment for acute cholecystitis after covered SEMS placement for distal MBO; however, cholecystitis recurrence should be taken into consideration.
Gallstones are a common health problem and have been diagnosed since the ancient world. Today, 20% of the population encounters a biliary tract pathology at some point in their life. Although 140 years have passed since Langenbuch’s first recipe for cholecystectomy in 1882, there was not much change in surgical technique. However, biliary tract surgery has developed with great advances in laparoscopic, endoscopic, radiological, and minimally invasive procedures. As a result of advances in diagnostic tools, many biliary pathologies are detected earlier. This early detection has led the clinicians to reevaluate the indications for surgery and also to search whether some conditions can be prevented by surgical removal before they develop. On the other hand, biliary tract traumas have become more common than ever before due to increasing initiatives with the contribution of developing technologies. New horizons have been opened in hepatobiliary surgery with three-dimensional imaging, navigation techniques, robotic surgery, and hybrid operating theaters. With the advances in embolization, stenting, and drainage techniques, more comprehensive and more tissue/organ protective procedures have been started.
La enfermedad de la vesícula por presencia de cálculos es muy frecuente en el mundo, su incidencia puede diferir de un país a otro, pero lo que sí se puede afirmar es que es más frecuente entre los 30 a 69 años y con una incidencia general de la enfermedad de cálculos biliares promedio de 19% en mujeres y 10% en hombres.
Acute cholecystitis (AC) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information available on its clinical features, outcomes, and risk management strategies. This retrospective, nested, case-control study included 6701 patients undergoing allo-HSCT at our center from January 2004 to June 2019. In total, 72 (1.1%) patients were diagnosed with AC. Acute acalculous cholecystitis (AAC) had a slightly higher prevalence in 42 (58.3%) patients. Patients with moderate and severe AC exhibited remarkably worse overall survival (OS, p = 0.001) and non-relapse mortality (NRM, p = 0.011) than others. Haploidentical HSCT recipients with AC had comparable survivals as those with HLA identical donors. Age≥18, antecedent II-IV aGVHD, and total parenteral nutrition (TPN) were identified as potential risk factors for AC following allo-HSCT, while haploidentical transplantations were not more susceptible to AC than HLA identical HSCT. Based on these criteria, a risk score model was developed and validated to estimate the probability of AC following allo-HSCT, which separated all patients into low-, intermediate-, and high-risk groups and thereby provided the basis for the early detection of this complication in the management of allo-HSCT.
Introduction:
Critical care patients have many risk factors for acute cholecystitis (AC). However, less data are available regarding newly developed AC in critically ill patients.
Objectives:
To investigate the clinical features of AC occurring in critically ill patients after admission to an intensive care unit (ICU).
Methods:
We performed a retrospective cohort study from January 2006 to August 2016 at a tertiary care university hospital. We included patients diagnosed with AC with or without gallstones after ICU admission. All cases of AC were confirmed by gastroenterologists or general surgeons. We excluded patients with AC diagnosed before or at the time of ICU admission.
Results:
A total of 38 patients were diagnosed with AC after ICU admission between January 2006 and August 2016. Seventeen (44.7%) had acute acalculous cholecystitis, while 21 (55.3%) had acute calculous cholecystitis. The median age was 73 years (interquartile range = 63-81 years), and 22 (57.9%) patients were male. The most common reason for ICU admission was pneumonia or sepsis. The median interval from ICU admission to diagnosis of AC was 11 days (interquartile range = 4.8-22.8 days). Before AC diagnosis, almost 90% of patients used total parenteral nutrition, 68% used opioids, 76% were mechanically ventilated, and 42% received vasoactive drugs. More than half of patients underwent cholecystectomy, and all surgically resected gallbladders had pathology results for cholecystitis. Gangrenous cholecystitis was observed in five patients with acute calculous cholecystitis. The overall mortality was 42.1%, and 1/3 of these deaths were directly associated with AC. The average length of stay in the ICU and hospital was 26.5 and 44.5 days, respectively.
Conclusion:
The development of AC in the ICU should be carefully monitored, especially in patients who have been infected and admitted to the ICU for more than 10 days. Proper diagnosis and treatment at a critical time could be lifesaving.
On January 1, 2011, the first of the Baby Boomers will turn 65 years old. And so will begin the largest increase in the number of older adults ever seen. To put this in perspective, in the entire history of mankind, two-thirds of all people who have ever lived to the age of 65 are alive today [1]. Advances in pharmacotherapy are partially responsible for this unprecedented increase in longevity and will play a central role in reducing morbidity and mortality in this aging cohort. However, when it comes to older adults, medications are often improperly dosed, overprescribed, and poorly monitored for signs of toxicity. Furthermore, changes in pharmacokinetics associated with aging leave little room for error. Surgeons operating on elderly patients should preoperatively identify potential medication-related problems (MRPs) that can result in postoperative complications. This chapter reviews some of the factors that contribute to MRPs in the elderly, general approaches to prescribing, signs and symptoms to monitor, and highlights of certain drug categories that are commonly used or have substantial potential to cause side effects in older adults.
Although elderly persons tend to be more sensitive to the effects and side effects of medications, most drugs are well tolerated if used judiciously. This chapter reviews some of the factors that contribute to this sensitivity, general approaches to prescribing, signs and symptoms to monitor, and highlights of certain drug categories that are commonly used or have substantial potential to cause side effects.
The chapter discusses drug-induced changes in the liver and pancreas. As the principal organ of drug metabolism and detoxification, hepatic toxicity remains a challenge to contemporary hepatology for a number of reasons. Drugs can cause fulminant hepatic failure. A drug-induced hepatic injury appears to account for more than 50% of the cases of acute hepatic failure. Some reactions recorded in humans are considered predictable as they are dose and time dependent. Reactions that occur with agents such as halothane, tienilic acid, and dihydralazine are believed to occur through immune-mediated mechanisms. Although hepatocytes have a fairly uniform structure, findings show that they possess considerable functional heterogeneity within the hepatic lobule. Periportal hepatocytes are well endowed with protective properties against reactive products such as superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals. This is evident by the presence of abundant glutathione and glutathione peroxidase in the periportal zones. The liver represents the principal organ of biotransformation, and hepatic oxidation is a major drug metabolizing process carried out by the cytochrome P450 monooxygenase system. The chapter explains how sex hormones also modify liver function in humans and that the influences of these hormones are potentially important in preclinical studies.
La epidemiología es el estudio de las variables o factores que condicionan la salud y la enfermedad de las poblaciones humanas. Estos factores son múltiples y de muy variada naturaleza: genéticos, laborales, nutricionales, tóxico-ambientales, psicosociales, etc. La farmacología clínica y la epidemiología del medicamento estudian los efectos de los medicamentos sobre el binomio salud-enfermedad, en este contexto multifactorial. Los fármacos son uno de los factores que el sistema sanitario utiliza con la finalidad de actuar sobre la salud de las poblaciones. Sin embargo, en muchas ocasiones este objetivo no se cumple. La epidemiología y la farmacología clínica se diferencian, por lo tanto, en el objeto principal de estudio, pero comparten objetivos secundarios y métodos de trabajo. Como ramas de la ciencia que son, evalúan hipótesis científicas habitualmente planteadas como proposiciones cualitativas. Estas, formuladas en forma de hipótesis nula, deben ser fácil y claramente refutables y en consecuencia (siguiendo la terminología de Popper) deben poseer un elevado «contenido empírico».
Se dice que las reacciones adversas producidas por medicamentos son tan antiguas como la misma historia y es lógico que así sea si se tiene en cuenta que cualquier producto con actividad farmacológica potencial puede actuar como un remedio pero también como un veneno. En cualquier caso las primeras encuestas formales de la era contemporánea sobre problemas de seguridad de medicamentos datan de finales del siglo pasado, cuando se formó una comisión encargada de estudiar los casos de muerte súbita ocurridos en pacientes anestesiados con cloroformo 1 o cuando se formó otra encargada de examinar los casos de ictericia entre pacientes sifilíticos tratados con arsenicales. 2 Eso no significa que las reacciones adversas producidas por medicamentos fueran des-cubiertas de manera más o menos rápida: transcurrieron casi 50 años desde la introducción de la amidopirina en terapéutica hasta que se descubrió que podía producir agranulocitosis 3 y 39 desde la introducción del ácido acetilsalicílico hasta que se descubrió que podía ser causa de hemorragia gastrointestinal. 4 La tragedia de las muertes producidas por el jarabe de sulfanilamida que contenía dietilenglicol (véase el Capítulo 1) y la epidemia de focomelia y otras malformaciones producidas por la talidomida 5 (véase también el Capítulo 1) son los hechos que más han contribuido a concienciar de la necesidad de definir, cuantificar, estudiar y prevenir los efectos indeseables de los medicamentos. Las reacciones adversas por medicamentos constituyen por lo tanto un tema de preocupación más o menos reciente: la epidemia de focomelia se produjo en 1960-1962. Entre otros factores, éste ha sido quizá uno de los más importantes que ha condicionado que en la actualidad el interés principal de la farmacología clínica se deba centrar en la selección de medicamentos partiendo de los conceptos de eficacia, relación beneficio-riesgo y relación beneficio-coste (véanse también los Capítulos 1, 2 y 3).
Pathology represents a challenge for everybody involved in drug development. Even trained pathologists with expertise in toxicological pathology have to make the difficult prediction of whether any drug induced pathology in animals is likely to occur in humans. If so, are rodents or dogs likely to be more or less sensitive to the adverse effects of drugs than patients? Do the pathology findings completely preclude giving a new drug safety to humans? In order to aide researchers with these tough decisions, the author has compiled this valuable reference.
The new 4th edition of Histopathology of Preclinical Toxicity Studies is now completely in full color and continues to describe the pathology found in drug safety studies in laboratory animals with an evidence-based discussion of the relevance of these findings to the clinical investigation of new drugs for humans. Organized according to organ systems, this revision features a thoroughly updated bibliography and discusses new drug-induced pathologies and applicable species comparisons to aid in the preclinical safety assessment of new medicines. This updated reference is essential for those involved in drug safety evaluation, including pathologists, toxicologists and pharmacologists working in corporate, government, academic and research settings. NEW TO THE FOURTH EDITION: *This edition is in full color and features nearly 200 high-quality images *Provides extended commentary on the relevance of pathological findings and features a fully updated bibliography containing sources for further reading *Includes new content coverage on the commonly used transgenic animal models that are used in safety assessment, specific tumor types induced by drugs in rodents, and new drug-induced pathologies and lesions.
Development of cholecystitis in patients with malignancies can potentially disrupt their treatment and alter prognosis. This review aims to identify antineoplastic interventions associated with increased risk of cholecystitis in cancer patients.
A comprehensive search strategy was developed to identify articles pertaining to risk factors and complications of cholecystitis in cancer patients. FDA-issued labels of novel antineoplastic drugs released after 2010 were hand-searched to identify more therapies associated with cholecystitis in nonpublished studies.
Of an initial 2,932 articles, 124 were reviewed in the study. Postgastrectomy patients have a high (5-30 %) incidence of gallstone disease, and 1-7 % develop symptomatic disease. One randomized trial addressing the role of cholecystectomy concurrent with gastrectomy is currently underway. Among other risk groups, patients with neuroendocrine tumors treated with somatostatin analogs have a 15 % risk of cholelithiasis, and most are symptomatic. Hepatic artery based therapies carry a risk of cholecystitis (0.02-24 %), although the risk is reduced with selective catheterization. Myelosuppression related to chemotherapeutic agents (0.4 %), bone marrow transplantation, and treatment with novel multikinase inhibitors are associated with high risk of cholecystitis.
There are several risk factors for gallbladder-related surgical emergencies in patients with advanced malignancies. Incidental cholecystectomy at index operation should be considered in patients planned for gastrectomy, and candidates for regional therapies to the liver or somatostatin analogs. While prophylactic cholecystectomy is currently recommended for patients with cholelithiasis receiving myeloablative therapy, this strategy may have value in patients treated with multikinase inhibitors, immunotherapy, and oncolytic viral therapy based on evolving evidence.
Zusammenfassung Malariaprophylaxe mit Mefloquin (Lariam®) kann zu unerwünschten Nebenwirkungen führen. Wir berichten über eine 42-jährige Patientin weißer Hautfarbe, die 7 Tage nach Urlaubsreise in Tansania mit schmerzlosem Ikterus und erhöhten Leber-, Cholestase- und Entzündungsparametern stationär aufgenommen wurde. Eine sonographisch diagnostizierte akute Cholezystitis wurde zunächst erfolglos mittels parenteraler Ernährung und antibiotischer Therapie behandelt. Nach Ausschluss von Infektionserkrankungen führte der Abbruch der Malariaprophylaxe erfreulicherweise zu einem Abfall der erhöhten Laborparameter, und auch sonographisch stellte sich wieder ein Normalbefund dar.
Fibrate derivatives and HMG-CoA reductase inhibitors modify homeostasis of cholesterol. The aim of this study was to assess in an unselected population whether these hypolipidemic drugs are risk factors for cholelithiasis or, conversely, are protective agents. Both sexes, all socioeconomic categories, pregnant women, and cholecystectomized subjects were included. Clinical data collection and gallbladder ultrasonography were both carried out in a double-blind fashion. Fibrate derivatives were predominantly fenofibrate, HMG-CoA reductase inhibitors were simvastatin and pravastatin. On univariate analysis, age (>50 years), sex, and use of fibrates were found to be significantly related to the presence of cholelithiasis. Age, sex, and fibrate treatment remained independently correlated with the presence of gallstones on multivariate analysis. With fibrates, the relative risk for lithiasis was 1.7 (P = 0.04). The HMG-CoA reductase inhibitors were not associated with a protective effect on univariate analysis. Of the lipid-lowering drugs, only fibrate derivatives were found to increase the risk of gallstone formation.
Older individuals in general take more medications than other age groups and are more susceptible to potential adverse effects.
This chapter reviews the changes that occur with aging and that underlie this increased susceptibility and offers suggestions
to minimize adverse effects. Specific medication categories are highlighted that pose particular risk of adverse effects in
older cardiothoracic surgery patients. The vast majority of medications can be used safely and effectively in older patients
if appropriate precautions are taken in the selection, dosing, and timing of medications, and in the active monitoring of
therapeutic effects and side effects.
KeywordsElderly/aging-Cardiothoracic surgery-Medications-Biology of aging-Pharmacokinetics-Polypharmacy-Delirium-Psychoactive medications-Antibiotics-Side effects
Introduction:
Beta-lactam antibiotics are among the most clinically useful antimicrobials used in medicine. Unfortunately, adverse events related to their use remain poorly understood by many clinicians and, in particular, the misdiagnosis of β-lactam allergy and misunderstanding of crossreactivity among members of the β-lactam antibiotics may effectively eliminate a whole class of antimicrobials from use and require the use of broader spectrum agents with less well-established safety profiles.
Areas covered:
This review describes the range, diagnosis and management of adverse events associated with β-lactam antimicrobials, particularly focusing on recognition, diagnosis and management of true allergy and risk of cross-sensitivity between β-lactam antibiotics. A literature review was undertaken using PubMed, focusing primarily on literature published in the past 10 years relating to β-lactam adverse events and allergy.
Expert opinion:
Beta-lactams are generally safe drugs and serious adverse events are rare and allergy is overdiagnosed. Accurate diagnosis can usually be achieved through careful history and in some instances skin or in vitro testing is required. Even among individuals with true immediate-type allergy to penicillin, most cephalosporins are readily tolerated and desensitization is usually an option in cases where no alternate antimicrobials are available. Other allergic reactions (Type II, III and IV) are rare and avoidance of the culprit agent is generally recommended. Nonallergic or morbilliform rashes are generally not allergic in nature and should not prompt drug or class avoidance. Other adverse events are frequently dose-related and can be avoided by appropriate dosing and consideration of renal function.
This is a case study of an infant with major congenital heart disease which illustrates problems encountered with a dynamic and changing pre-operative clinical picture and subsequent late and unexpected complications of cardiac surgery. This study will demonstrate the importance of appropriate investigations based on good clinical reasoning and working within a managed clinical network. The study is divided into three parts depending on the colour (clinical system affected) with which the child presented.
To update readers on the pharmacotherapeutic management of cryptosporidiosis in patients with AIDS.
A MEDLINE search was used to identify pertinent literature. Additionally, programs and abstracts from the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy; the 1st International Conference on Macrolides, Azalides, and Streptogramins; the 93rd American Society for Microbiology Meeting; and the 6th and 7th International Conferences on AIDS were used.
Available data from in vitro, animal, and human experiments were reviewed.
Intestinal cryptosporidiosis in patients with AIDS can be a life-threatening opportunistic infection. However, there can be significant variability in disease expression, including spontaneous remission. Supportive care with hydration and nutritional supplementation remains a hallmark of therapy. Unfortunately, there is no proven specific pharmacotherapy of cryptosporidiosis in patients with AIDS. Numerous agents have been analyzed for in vitro activity and efficacy in experimental animal models and actual human cases of the infection, including paromomycin, azithromycin, clarithromycin, octreotide, hyperimmune bovine colostrum, bovine transfer factor, and many others. Because limited numbers of controlled trials have been conducted with potential therapeutic agents, the majority of the information to date is preliminary in nature.
Despite the availability of some evolving and potentially promising treatment modalities, further controlled clinical trials are necessary to evaluate the role of pharmacotherapy for intestinal cryptosporidiosis in patients with AIDS.
Recent advancements in liver transplantation have resulted in extended survival both for grafts and recipients. Such improvement, together with the shortage of donor organs has prompted expansion of the donor pool to include less than ideal donors, especially in life-threatening situations. The use of older liver donors has been associated with lower long-term survival. However, potential morbidity such as gallstone formation has not been explored. We analyzed bile composition in a child who developed cholesterol gallstones in the proximal bile duct two years after undergoing emergency liver transplantation with a liver from a 78-year-old donor. Oral administration of ursodeoxycholic acid (ursodiol) shifted the cholesterol composition of the bile from a supersaturated, potentially crystallized state to a liquid (micellar) state. Unlike cyclosporin A, FK506 showed an increase in the proportion of chenodeoxycholic acid and a decrease in the proportion of cholic acid, and thus may exhibit minimal or no hepatotoxic effect. Thus, in donor livers with factors known to be associated with cholesterol gallstone formation (such as age, sex, or obesity), one may consider analyzing the bile composition at the time of procurement. Depending on cholesterol and bile acid composition the use of FK506 with or without addition of ursodeoxycholic acid may be warranted.
Using a statewide hospital discharge database and a novel epidemiology method, sequence symmetry analysis (Epidemiology. 1996;7:478-84), I examined the relative risk for hospital admission for acute cholecystitis after admission for myocardial infarction. In sequence symmetry analysis, the ratio of the number of subjects in a fixed population who experienced two events in a "causal" vs "noncausal" temporal sequence estimates the incidence rate ratio (IRR). Of 514 patients admitted for both myocardial infarction and acute cholecystitis during a 3-year window period, 295 were admitted for myocardial infarction first and 219 for acute cholecystitis first, yielding a null sequence-adjusted IRR of 1.45 [95% confidence interval (CI) = 1.28-1.64]. A similar analysis for a known relation (myocardial infarction-->congestive heart failure, N = 27,850) showed the expected association [adjusted IRR = 1.92 (95% CI = 1.88-1.95)], whereas an analysis for a relation hypothesized not to be strong (congestive heart failure-->acute cholecystitis, N = 775) showed only a small association [adjusted IRR = 1.16 (95% CI = 1.05-1.28)]. Subgroup analysis revealed time courses that supported each relation as causal. Hospitalization for myocardial infarction may increase the risk for subsequent hospitalization for acute cholecystitis.
The prolonged biological half-life of Ceftriaxone, allowing once-daily dosing, has contributed to the large diffusion of this third-generation cephalosporin in children. Ceftriaxone is known to induce reversible precipitates in the gallbladder of adults and children. A prospective study was conducted during 1997 in 34 children admitted for the treatment of acute pyelonephritis. Ceftriaxone (intravenous daily single-dose of 50 mg/kg under 2g/day) was initially used. A first gallbladder sonogram, performed before the first or second injection, was normal in all cases. A second evaluation was performed before the fifth and last injection. On this second evaluation the presence of one (n = 3) or two gallstones was recorded in 5 children (15%) on a sonogram made after 3 (n = 4) or 5 (n = 1) injections. Their median age was 7 years (range 4 months to 11 years). All five children remained symptom-free and the normalization of the sonographic patterns was constant on the last sonogram performed 2 (n = 1), 3 (n = 2) and 5 months (n = 2) after discontinuation of Ceftriaxone. This study confirms the possibility of precocious biliary lithiasis under Ceftriaxone therapy in childhood and their spontaneous dissolution after discontinuation of the drug. They seem unpredictable and independent of the age, sex in a cohort homogeneous for the nature of the infection, modality of a short- and low-dose therapy. Clinicians and radiologists should be aware of this complication as an etiology of a so-called primary cholelithiasis and to prevent anxiety or unnecessary cholecystectomy. The antibacterial and pharmacokinetic benefits of Ceftriaxone outweigh the problem of reversible biliary pseudolithiasis with this drug.
Biliary excretion is a significant component in the metabolism of many drugs, but remains difficult to detect and characterise non-invasively. A previous publication recently described the detection of metabolites of ifosfamide in gall bladder in a guinea pig model using in vivo 1H-decoupled 31P 3-D magnetic resonance spectroscopic imaging and a clinical 1.5 T MR scanner.. Here high-resolution 31P magnetic resonance spectroscopy (MRS) of extracted bile identifies peaks as parent ifosfamide (1.19+/-1.47 mM; mean+/-sd), carboxyifosfamide (2.04+/-1.04 mM) and a major contribution from a previously unreported peak at 16.0 ppm (4.05+/-2.38 mM). The unknown resonance was identified using liquid chromatography-mass spectrometry (LCMS) as the glutathione conjugate of ifosfamide (MW=531). This was confirmed by analysing products from the reaction of glutathione with ifosfamide using LCMS and MRS. These results demonstrate how combined in vivo and analytical MRS, together with mass spectrometry, can help identify visceral routes of drug metabolism, thereby aiding understanding of +/-drug disposition and mechanisms of action and toxicity. In particular, the distribution of ifosfamide and its metabolites into bile may be related to oxazophosphorine-related cholecystitis reported in patients.
The side effects caused by malaria prophylaxis with mefloquine (Lariam) are well known. We describe the case of a 42-year-old female Caucasian patient suffering from painless jaundice and showing elevated liver, cholestasis and inflammation laboratory findings 7 days after returning from Tanzania. Acute cholecystitis was diagnosed by ultrasound. Treatment with parenteral nutrition and antibiotic therapy did not show any beneficial effect. Excluding the possibility of infectious diseases, the elevated laboratory and ultrasound findings were normalized after the discontinuation of the malaria prophylaxis.
Ceftriaxone is a commonly used third-generation cephalosporin that has antimicrobial activity against many gram-positive and gram-negative organisms. Generally, ceftriaxone is a safe antibiotic; however, symptomatic biliary sludge has been reported in rare instances, most of which have involved children. It is uncommon for ceftriaxone to cause increases in laboratory indexes, such as bilirubin levels. We describe the case of a 53-year-old man who was treated with intravenous ceftriaxone 2 g every 12 hours. After 7 days of therapy, the patient's liver function test results, including total, direct, and indirect bilirubin levels, increased significantly from baseline, and the patient became jaundiced. A right upper quadrant ultrasound examination revealed biliary sludge and cholelithiasis without sonographic evidence of cholecystitis. Ceftriaxone was thought to be the responsible agent, and it was discontinued. The patient's jaundice subsided, and his liver function test results improved, returning to baseline within 14 days. Clinicians need to be aware of the association of ceftriaxone and biliary pseudolithiasis and hyperbilirubinemia, and monitor accordingly.
Acute cholecystitis is one of the most frequent complications in gallstone disease. Recently, new diagnosis criteria and severity assessment score have been defined and allow adequate treatment of each category. Early laparoscopic cholecystectomy is the treatment of choice in mild and moderate cholecystitis. In severe cholecystitis primary stabilization of organ failure is recommended as well as urgent cholecystectomy or percutaneous drainage of the gallbladder.
Nine patients with heterozygous familial hypercholesterolaemia were treated for eight weeks with either 40 mg pravastatin or placebo under double blind conditions. Six patients received pravastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Treatment with pravastatin resulted in a significant decrease in plasma cholesterol caused by a decrease in low density lipoprotein cholesterol (LDL-c) of 30% (p less than 0.005). We determined the effect of this medication on the lithogenicity of bile. Cholesterol saturation index of fasting gall bladder bile decreased with 23% (p less than 0.01) from 1.06 to 0.75 during treatment with pravastatin. A reduction of 24% (p less than 0.01) in molar percentage of biliary cholesterol was seen. After treatment the total bile acid excretion in faeces and the molar percentage of biliary bile acids were not significantly changed, suggesting that pravastatin does not influence bile acid biosynthesis to a significant extent. These findings indicate that treatment with pravastatin can decrease the incidence and complications of cholesterol gall stones.
To compare ceftriaxone with cefuroxime for the treatment of meningitis, we conducted a study in which 106 children with acute bacterial meningitis were randomly assigned to receive either ceftriaxone (100 mg per kilogram of body weight per day, administered intravenously once daily; n = 53) or cefuroxime (240 mg per kilogram per day, administered intravenously in four equal doses; n = 53). The mean age of the children was 3 years (range, 42 days to 16 years), and the characteristics of the two treatment groups were comparable at admission. Excluded from the study were eight other children who died within 48 hours of admission. After 18 to 36 hours of therapy, cultures of cerebrospinal fluid remained positive for 1 of the 52 children (2 percent) receiving ceftriaxone for whom cultures were available and 6 of 52 (12 percent) receiving cefuroxime (P = 0.11). In both groups the mean duration of antibiotic therapy was 10 days. The clinical responses to therapy were similar in the two treatment groups, and all 106 children were cured. Reversible biliary pseudolithiasis was detected by serial abdominal ultrasonography only in the children treated with ceftriaxone (16 of 35 vs. 0 of 35; P less than 0.001). The treatment of three children was switched from ceftriaxone to alternative antibiotics because these children had upper abdominal pain. Other side effects were infrequent in both groups. At follow-up examination two months later, moderate-to-profound hearing loss was present in two children (4 percent) treated with ceftriaxone and in nine (17 percent) treated with cefuroxime (P = 0.05); other neurologic abnormalities were similar in the two treatment groups. We conclude that ceftriaxone is superior to cefuroxime for the treatment of acute bacterial meningitis in children and that the benefits of milder hearing impairment and more rapid sterilization of the cerebrospinal fluid with ceftriaxone outweigh the problem of reversible biliary pseudolithiasis with this drug.
To assess if and by which mechanisms pharmacological estrogen treatment induces gallstone disease, we examined patients with recently diagnosed prostatic cancer randomly allocated to estrogen therapy (n = 37) or orchidectomy (n = 35). According to gallbladder ultrasonography, after 1 yr new gallstones had developed in 5 of 28 estrogen-treated patients, compared with 0 of 26 orchidectomized patients (P = 0.03). Estrogen therapy for 3 mo increased the relative concentration of cholesterol and cholesterol saturation of bile by approximately 30% (n = 10). Serum LDL cholesterol was reduced by approximately 40%, and its relative change related inversely to that of bile cholesterol (Rs = -0.77). There were no changes in biliary or serum lipids after orchidectomy (n = 9). Secretion rates of biliary lipids were measured with a duodenal perfusion technique. Patients on chronic estrogen therapy (n = 5) had approximately 40% higher biliary excretion rates of cholesterol than age-matched controls (n = 7). Phospholipid secretion was also higher, but no difference in bile acid secretion was found. We conclude that an increased hepatic secretion of cholesterol results in increased cholesterol saturation of bile and an enhanced rate of gallstone formation during estrogen treatment. The changes in bile cholesterol seem to be related to the induced changes in serum lipoprotein metabolism.
To characterize the effects of estrogen treatment on the metabolism of LDL we studied six males with metastatic prostatic carcinoma before and during the initiation of therapy; a repeated study was performed in five participants after 3-6 mo of treatment. The fractional catabolic rate (FCR) of autologous 125I-LDL was calculated both from elimination curves of plasma radioactivity and from urine/plasma (U/P) radioactivity ratios. Within 1-2 d of onset of estrogen therapy a more rapid decay of plasma radioactivity occurred, and FCR measured from U/P ratios increased by 20%. Concomitantly, LDL cholesterol levels decreased by 16%. After 3-6 mo of treatment FCR determined by both techniques was almost doubled, and LDL cholesterol was reduced by 34%. This occurred despite a 29% increase in the calculated synthesis rate of LDL. Tissue culture studies demonstrated that the receptor affinity of LDL isolated from patients on long-term estrogen therapy was reduced. We conclude that a profound increase in LDL catabolism is induced through administration of pharmacological doses of estrogen in males, and hypothesize that this is the consequence of an increased expression of hepatic LDL receptors. This enhanced catabolism of LDL leaves LDL particles in plasma with lower affinity for the LDL receptor.
Recent repopularization of intrahepatic infusion chemotherapy has been made possible by the development of the implantable Infusaid pump. Surgical placement of a catheter into the gastroduodenal artery with division of collaterals to the stomach, duodenum, and pancreas has reduced the incidence of gastroduodenal ulceration and pancreatitis. The risk of chemical cholecystitis similarly demands prevention. Anatomically, the cystic artery is a branch of the right hepatic artery in over 95 percent of patients. As a result, even a normal gallbladder is subjected to high-dose chemotherapy with the risk of development of drug-induced cholecystitis. In our first six patients undergoing pump implantation who had normal appearing gallbladders at the time of surgery, two developed symptomatic cholecystitis, necessitating cholecystectomy after receiving intrahepatic chemotherapy. As a result, we recommend elective cholecystectomy at the time of arterial catheterization for intrahepatic chemotherapy.
1.
Acute cholecystitis is usually dependent on an obstruction to the outlet of the gall bladder with interruption in the blood
supply to the organ. In over 92 per cent of cases the obstructing agent is a calculus. Secondary infection of the ischemic
areas may or may not occur.
2.
Acute cholecystitis is a dangerous condition. Under conservative treatment perhaps 25 per cent of the patients will get worse.
Serious complications such as empyema, gangrene, perforation of the gall bladder and generalized peritonitis frequently occur.
3.
Unfortunately in these cases there is no good correlation between the severity of the clinical manifestations and the severity
of the disease. Furthermore, it is impossible to predict in any one case whether the disease will quiet down or get worse.
4.
Statistics show that the mortality is great in the “early” operations done after the symptoms have been present for forty-eight
hours. Operations done within forty-eight hours after the onset of the acute attack have had the lowest mortality rate. Unfortunately
few patients reach a hospital within this interval.
5.
It is inadvisable, however, to operate on every patient seen within forty-eight hours after the onset of acute symptoms. If
such an early operation is done as a routine many diagnoses will be wrong and patients will be operated on unnecessarily.
6.
Patients and the disease vary widely, and hence the treatment must be individualized.
7.
A plan of procedure which has been employed successfully in the management of patients with acute cholecystitis is outlined.
In response to three reports of an association between rauwolfia derivatives and breast cancer, a case/control study was undertaken in Olmsted County, Minnesota. Comparison of a cohort of women with breast cancer to an age-match cohort of women with cholelithiasis failed to show any meaningful differences in the two groups except with respect to a history of hypertension. The rates of use of rauwolfia derivatives by hypertensive cases and controls were identical--which, along with other considerations, leads to the conclusion that an association between the use of rauwolfia derivatives and breast cancer is unlikely.
A causal relationship between the use of oral contraceptives and gallstone disease has been proposed. If this is true, it is reasonable that the incidence of cholecystectomy in women of exposed ages should increase. In the present study a statistical analysis of the change in the incidence of cholecystectomy in women between 1961, i.e. 4 years before, and 1971, i.e. 6 years after, the introduction of oral contraceptives in Sweden was performed. To delimit uncontrolled factors, such as diet and attitude towards surgery, the change in incidence of cholecystectomy in women was compared with the corresponding change in men during these years. The results indicate an increased incidence of cholecystectomy in women in age groups exposed to oral contraceptives. These findings support a causal relationship between the use of oral contraceptives and the incidence of gallstones in the population.
In view of the reported association between use of oral contraceptives and gallbladder disease, the effects of contraceptive steroids on the lipid composition of gallbladder bile were studied in 22 healthy women. Each subject was studied during routine use of oral contraceptives and also during normal menstrual cycles on no medication. Gallbladder bile was significantly more saturated with cholesterol during contraceptive therapy than during normal menstrual cycling (125 versus 92 per cent, P less than 0.001). Chenodeoxycholic acid accounted for a significantly smaller proportion (35 versus 42 per cent P less than 0.001) and cholic acid a significantly greater proportion (50 versus 41 per cent (P less than 0.001) of total bile acids during contraceptive steroid therapy. These findings show that exogenous sex steroids in doses and formulations routinely prescribed induce important alterations in the composition of human gallbladder bile, and suggest a biochemical basis for the increase in gallbladder disease observed among women using oral contraceptives.
Long-term administration of the somatostatin analogue, octreotide, is complicated by gallstone formation. Somatostatin is known to inhibit hepatic bile secretion and gallbladder emptying. However, the effect of octreotide on gallbladder bile composition remains unknown. Therefore, we tested the hypothesis that octretide would alter hepatic bile composition and cause gallbladder stasis, thereby increasing gallbladder bile solute concentrations. Fourteen control prairie dogs received daily saline injections, whereas 10 animals received 1 micrograms of octreotide subcutaneously three times per day for 5 days. Cholecystectomy and common bile duct cannulation were then performed. Octreotide increased hepatic bile concentrations of bilirubin monoglucuronide (p less than 0.05), total bilirubin (p less than 0.05), and total protein (p less than 0.01). Rsa, an index of gallbladder stasis, was decreased (p less than 0.01) in the octreotide group. Gallbladder bile total calcium (p less than 0.05), bilirubin monoglucuronide (p less than 0.05), total bilirubin (p less than 0.01), total protein (p less than 0.05), and total lipids (p less than 0.05) were increased in the octreotide group. Animals receiving octreotide also had decreased hepatic (p less than 0.05) and gallbladder (p less than 0.001) bile pH. No differences in cholesterol saturation index were observed. These data suggest that in the prairie dog, octreotide (1) alters hepatic bile composition, (2) causes gallbladder stasis, and (3) increases gallbladder bile calcium, bilirubin, protein, lipid, and hydrogen ion concentrations. We conclude that octreotide causes alterations in gallbladder bile composition that increase the likelihood of cholesterol and calcium bilirubinate precipitation.
Various lipid-lowering drugs have been shown to reduce serum cholesterol and serum triglycerides effectively. In view of trials indicating that lipid-lowering drugs may reduce cardiac morbidity and mortality but not the overall mortality in the study group, increased attention must be focused on potential harmful side effects during treatment with these agents.
The adverse effects of many of the principal drugs in this category are discussed. Gastrointestinal symptoms, usually self-limited and reversible, are the most common side effects. Potential harmful adverse effects include drug interactions (cholestyramine), myopathy and hepatic injury (HMG-CoA reductase inhibitors), and increased gallstone formation and ventricular arrhythmias (clofibrate).
Not all lipid-lowering drugs have been studied adequately on a long term basis, so that medications given for an indefinite period must be reevaluated frequently. However, there are several agents that lower serum lipid levels effectively and that have been used for more than 20 years without serious side effects.
Patients with non-insulin dependent diabetes mellitus have an increased incidence of coronary artery disease which may, in part, be associated with abnormalities in plasma lipids. In a double-blind, parallel, randomized study, lovastatin and gemfibrozil were compared in 102 diabetic patients with primary hypercholesterolemia; two-thirds of the patients were treated with oral hypoglycemic agents and one-third received diet therapy alone for their diabetes. Mean pretreatment total and low-density lipoprotein (LDL) cholesterol values were 273 and 193 mg/dl, respectively. Lovastatin significantly reduced total, LDL and very low density lipoprotein cholesterol (20, 26 and 28%, respectively) and raised high-density lipoprotein (HDL) cholesterol (14%). Gemfibrozil significantly reduced triglycerides and very low density lipoprotein cholesterol (36 and 41%, respectively) and, to a lesser extent, total cholesterol (9%); it also increased HDL cholesterol (21%). Lovastatin therapy was not associated with a significant change in triglycerides, and gemfibrozil did not significantly lower LDL cholesterol. The decrease in the ratio of total to HDL cholesterol tended to be greater with lovastatin than with gemfibrozil (26.5 and 20.4%, respectively; p = 0.053). Changes in lipid profiles with both agents were of a degree similar to those reported in nondiabetic patients. Neither agent had a clinically important effect on fasting glucose or hemoglobin A1c. Both drugs were well tolerated with the exception of 2 patients treated with gemfibrozil who developed symptoms of cholecystitis.
Gastrointestinal side-effects of prolonged therapy (greater than 2 yr) with the long-acting somatostatin analog octreotide were studied in 10 acromegalic patients. After 2 yr of therapy, 6 of 10 patients had newly developed gallstones, complicated by cholangitis and jaundice in 1. Serum vitamin B-12 concentrations declined in all 10 patients [from 380 +/- 32 to 172 +/- 21 pmol/L (mean +/- SE); P = 0.023] and became abnormally low in 4. Gastric biopsy specimens, obtained during gastroscopy (9 patients), showed moderate to severe active gastritis, with damage to the superficial and deeper layers of the mucosa in 9 of 9 and focal atrophy in 7 of 9 patients. Campylobacter pylori was found in the antral mucosa in 8 of 9 patients. Although information is lacking on similar studies in untreated acromegalic patients, we suggest that patients receiving chronic octreotide therapy be closely monitored for these and possible other side-effects related to gastrointestinal actions of octreotide.
A 65-year-old man on maintenance dapsone therapy for dermatitis herpetiformis for 30 years was admitted to hospital with acute abdominal pain and vomiting. Investigations revealed a Heinz body haemolytic anaemia. Worsening symptoms prompted an emergency laparotomy that revealed a perforated gall bladder with pigmented biliary calculi. In previous reviews of the haematological abnormalities associated with dapsone therapy, life-threatening cholecystitis has not been described.
Hepatic intraarterial injection of Lipiodol has been used by various authors to enhance the diagnostic accuracy of computed tomography in hepatic tumors. The technique appears safe and seems free from serious complications when used judiciously. We report a case in which injection of hepatic intraarterial Lipiodol precipitated acalculous cholecystitis requiring urgent laparotomy.
Somatostatin (SST) has been shown to induce cholestasis in the dog and in the rat. In man, it is still unknown whether SST modifies bile formation. The present study was undertaken to examine the influence of SST on bile secretion in man. Two volunteers who had a total external biliary fistula received 1-hour SST infusions (3.5 micrograms/kg/h). Bile flow, bile acid, phospholipid and cholesterol biliary outputs were measured before, during and 1 h after the infusion. The SST infusion was associated with a pronounced decrease in bile flow and in bile acid secretion and with an increase in bile cholesterol saturation. These findings suggest that SST has cholestatic properties in man as in other species. This may provide a rational explanation for the formation of gallstones and for the steatorrhea observed in patients with somatostatinomas or during therapeutic SST administration.
A case of infiltrative hematoma of the porta hepatitis and the gallbladder wall is reported. It is a rare complication of anticoagulant treatment. The sonographics findings were 1 degree an echogenic material surrounding the porta hepatis, and 2 degrees a gallbladder wall thickening. Both these lesions appeared as dense areas on computed tomography (CT) scan. The aetiologies of hemorrhagic cholecystitis are discussed.
The effect of the long-acting somatostatin analogue Sandostatin (SMS 201-995) on intestinal absorption and propagation (mouth-to-caecum transit time; MCTT), on pancreatic secretion and on gall bladder contraction after direct (secretin-pancreozymin test) and indirect stimulation (Lundh meal), and on meal-induced responses of seven gastrointestinal regulatory peptides has been investigated. In a double-blind cross-over study, 9 healthy volunteers completed two 7-day periods with subcutaneous injections of either placebo or 25 micrograms SMS 201-995 twice daily. Mean faecal fat excretion was increased to 19.2 g/day and MCTT was three times longer during the SMS period. After duodenal infusion of a mixture containing D-galactose, D-xylose and triglycerides, SMS 201-995 significantly reduced the serum concentrations of D-galactose but increased serum levels of D-xylose. After 6 days of pretreatment, SMS 201-995 completely suppressed duodenal trypsin, lipase and bilirubin increases in response to endogenous stimulation by a Lundh meal. Concomitantly, cholecystokinin (CCK) release and gall bladder contraction were almost abolished. Compared with placebo, SMS 201-995 significantly diminished pancreatic amylase, trypsin and lipase output after stimulation with CCK, while the secretion of fluid and bicarbonate in response to secretin was unchanged. This inhibition of enzyme response was significantly more marked after a single injection of the analogue than after pretreatment for 7 days and did not reach the level of exocrine pancreatic insufficiency. CCK-induced gall bladder contraction was significantly inhibited by a single dose of 25 micrograms SMS 201-995 but not after 7 days of pretreatment with the somatostatin analogue.
Serial abdominal ultrasonography was performed in 37 children being treated with ceftriaxone for serious infections. Biliary concrements developed in 16 patients, causing symptoms in 3, one of whom also had urolithiasis with renal colic and obstructive ureteropyelectasia. After cessation of ceftriaxone treatment, ultrasound abnormalities and symptoms gradually disappeared, with complete sonographic resolution after 2 to 63 days.
In a 1 year period, 13 patients underwent pump implantation for liver metastasis from a primary colorectal tumor. The gallbladders were not removed at the time of pump implantation in the initial six patients. In these patients, chemotherapy consisted of floxuridine given every 2 weeks followed by a 2 week rest period and cisplatin over 1 hour by way of the side portal on day 8 of the cycle. The treatment was repeated every 28 days. All patients whose gallbladders were not removed at the time of pump implantation required reoperation for acute or chronic acalculous cholecystitis from 1 to 9 months (mean 5.4 months) after pump implantation. At operation, all patients were found to have various degrees of inflammation and fibrosis. In one patient, significant sclerosing cholangitis was documented that involved the entire intrahepatic ductal system and hepatic duct bifurcation. Cholecystectomy and operative cholangiography are recommended in all patients who undergo pump implantation for metastatic disease to the liver.
This report centers on a patient with metastatic colorectal cancer who developed acute and chronic cholecystitis secondary to the infusion of FUDR (fluoro-deoxyuridine) into the hepatic artery. This was documented by sonography, cholescintigraphy, and, ultimately, pathologically on the surgically removed specimen. Undoubtedly, with increasing cumulative treatment days made possible through technological advances in delivery systems, this complication will be seen more frequently. Prophylactic removal of the gallbladder, at the time of pump placement, which does not significantly prolong the operative time nor increase the operative mortality, should be performed to prevent this complication from occurring.
The introduction of chemotherapeutic agents directly into the proper hepatic artery via an indwelling catheter results in perfusion of the gallbladder, because the cystic artery is usually a branch of the right hepatic artery. Five gallbladders, removed two to 16 months after insertion of permanently implanted Infusaid model 400 pumps, were examined. All of the gallbladders had significant arteritis, with narrowing or occlusion of lumina or necrosis of vessel walls. Fibrosis of the gallbladder wall was also a constant finding. Nuclear atypia of mucosal epithelium and connective tissue was common. Varying degrees of acute and chronic inflammation were present. These abnormalities may have a radiomimetic and direct irritant pathogenesis.
We tested the possibility that simvastatin, a competitive inhibitor of HMG-CoA reductase related to mevinolin, might alter cholesterol saturation of gallbladder bile. Ten patients with Type IIa or IIb hypercholesterolemia underwent bile sampling before, and again after, treatment with 20 or 40 mg per day simvastatin for 7 to 13 weeks. Mean cholesterol saturation index of gallbladder bile fell from 1.01 to 0.77 during simvastatin treatment (p less than 0.01). This finding strongly suggests that treatment with HMG-CoA reductase inhibitors will not predispose to development of cholesterol gallstones. Indeed, it raises the possibility that such inhibitors might have a future role to play in treatment of gallstones.
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Schaad UB, Tschappeler H, Lentze MJ. Transient formation of precipitations in the gallbladder associated with ceftriaxone therapy. Pediatr Infect Dis. 1986 Nov-Dec;5(6):708–710. [PubMed]
Hepatic artery infusion chemotherapy is used in the treatment of certain selected hepatic tumors, especially metastatic adenocarcinoma of the colon. Chemical cholecystitis has been recognized recently as a complication of hepatic artery infusion chemotherapy. We performed hepatobiliary scans on ten patients receiving hepatic artery infusion chemotherapy. All ten patients had abnormal hepatobiliary scintigraphy. We present case reports of three patients with abnormal hepatobiliary scans who have required cholecystectomy for symptoms of chemical cholecystitis to illustrate the clinical, scintigraphic, and pathologic findings in these patients.
From a cross sectional study of gall stone disease ascertained by ultrasonography, the prevalence in relation to age at menarche, use of oral contraceptives, childbirths, breastfeeding, abortions, age at menopause, and menopausal hormone therapy was assessed. The random sample comprised 2301 women of Danish origin aged 30, 40, 50, and 60 years, of whom 1765 (77%) attended the investigation. Gall stone disease was significantly associated with young age at menarche, abortions, and multiple childbirth. Use of oral contraceptives was significantly associated with gall stone disease in univariate analysis, but not in multivariate analysis. Breastfeeding, age at menopause and menopausal hormone therapy were not associated with gall stones. These determining variables seemed sufficient to explain the higher prevalence of gall stone disease in women than in men.
In a randomized, double-blind five-year trial, we tested the efficacy of simultaneously elevating serum levels of high-density lipoprotein (HDL) cholesterol and lowering levels of non-HDL cholesterol with gemfibrozil in reducing the risk of coronary heart disease in 4081 asymptomatic middle-aged men (40 to 55 years of age) with primary dyslipidemia (non-HDL cholesterol greater than or equal to 200 mg per deciliter [5.2 mmol per liter] in two consecutive pretreatment measurements). One group (2051 men) received 600 mg of gemfibrozil twice daily, and the other (2030 men) received placebo. Gemfibrozil caused a marked increase in HDL cholesterol and persistent reductions in serum levels of total, low-density lipoprotein (LDL), and non-HDL cholesterol and triglycerides. There were minimal changes in serum lipid levels in the placebo group. The cumulative rate of cardiac end points at five years was 27.3 per 1,000 in the gemfibrozil group and 41.4 per 1,000 in the placebo group--a reduction of 34.0 percent in the incidence of coronary heart disease (95 percent confidence interval, 8.2 to 52.6; P less than 0.02; two-tailed test). The decline in incidence in the gemfibrozil group became evident in the second year and continued throughout the study. There was no difference between the groups in the total death rate, nor did the treatment influence the cancer rates. The results are in accord with two previous trials with different pharmacologic agents and indicate that modification of lipoprotein levels with gemfibrozil reduces the incidence of coronary heart disease in men with dyslipidemia.
Two hundred twenty-eight patients from a total of 466 (49%) receiving renal allografts under cyclosporine/prednisone (CsA/Pred) immunosuppression experienced at least one episode of posttransplant hepatotoxicity. All patients were documented to have normal serum bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), lactic acid dehydrogenase (LDH), and alkaline phosphatase (AP), as well as negative results of biliary ultrasound and upper gastrointestinal contrast examinations prior to transplantation. Hepatotoxic episodes usually were self-limited (82%), and generally occurred during the very early posttransplant period (76%). Liver function abnormalities included hyperbilirubinemia (48% of patients), elevated SGOT (47%), SGPT (73%), LDH (84%), and AP (59%). The CsA serum trough radioimmunoassay (RIA) was relatively high among hepatotoxic patients with a mean value of 225 +/- 17 ng/ml. Pharmacokinetic parameters, including bioavailability and drug clearance, were significantly altered among this group of patients. The management strategy of CsA dose reduction was effective; however, 11 patients (2.4%) developed biliary calculous disease posttransplant while under CsA/Pred immunosuppression. Seven patients had cholelithiasis, and two patients underwent choledochoduodenostomy because of primary choledocholithiasis. The results contrast with 279 renal transplant recipients from an overlapping nonrandomized group treated with azathioprine (Aza)/Pred in whom cholelithiasis was not identified. Pancreatic abnormalities were relatively common, but clinical pancreatic disease occurred in only six patients. There were two episodes of acute pancreatitis, three patients developed pancreatic abscess, and one patient developed a pancreatic pseudocyst. The apparent proclivity of CsA-treated patients to develop biliary calculous disease, and the occurrence of serious pancreatic complications in a small percentage of patients did not affect the majority of CsA-treated patients. They may, however, represent important problems associated with the use of this immunosuppressive agent.
The prevalence of gallstone disease (cholelithiasis and previous cholecystectomy for gallstones) in the population of the town of Sirmione, Italy, examined by ultrasonography, was 6.7% in men and 14.6% in women, ranging from 18 to 65 yr of age (overall prevalence = 11%). The prevalence of cholelithiasis in the same age span was 6.9% (4.5% in men and 8.9% in women). Prevalence of cholelithiasis increased with age in both sexes.
Twenty-two percent of gallstone subjects suffered from biliary pain vs. 2% of subjects without gallstones. No difference was observed in the frequency of nonspecific symptoms between subjects with and without gallstones. Of the 132 gallstone subjects, 108 (82%) were not aware of having gallstones prior to the study.
Prevalence of gallstone disease was found to be higher in obese and hypertriglyceridemic subjects and to increase with the number of pregnancies.
The mechanisms of the lipid-lowering agent gemfibrozil on biliary lipid metabolism were studied in eight normolipemic male volunteers. These measurements were performed before and after 3 months of administration. During administration of gemfibrozil, plasma cholesterol decreased by 19% (P less than 0.01) and triglycerides by 46% (P less than 0.01), and HDL cholesterol increased by 10% (P less than 0.01). The lithogenic index in gallbladder bile increased from 0.73 to 1.37 (P less than 0.05) and in hepatic bile from 0.86 to 1.42 (P less than 0.01). The increase in lithogenicity of gallbladder bile and hepatic bile was due to an increased biliary output of cholesterol from 47 to 70 mg/h (P less than 0.01) and a decreased output of bile acids from 943 to 694 mg/hr (P less than 0.01), whereas phospholipid output was not altered. The reduction in bile acid output was a result of a significant decrease in chenodeoxycholic acid secretion (r = 0.852; P less than 0.01). Cholic acid output was not affected by gemfibrozil. These results suggest that administration of gemfibrozil enhances the possible risk of gallstone formation like clofibrate.
Nine cases of acute acalculous cholecystitis were diagnosed in the surgical intensive care unit at Hartford Hospital during a 2 year period after abdominal, cardiovascular, and traumatic surgery. A tender mass in the right upper quadrant was suggestive but not diagnostic of the condition. Hyperamylasemia was seen in all patients. Ultrasonography is the most useful diagnostic tool; serial studies reveal progressive gallbladder dilatation and edema. Tube cholecystostomy was used in five patients and cholecystectomy in four. Cholecystostomy led to resolution of the inflammatory process in all five patients. Cholecystectomy should be reserved for those patients with extensive gallbladder necrosis. Six of the nine patients in the series died, all from multiple systems failure with concomitant sepsis. Hypotension is probably central to the development of acute acalculous cholecystitis. In the face of elevated intraluminal gallbladder pressure caused by ampullary edema and increased bile viscosity, hypotension may result in mucosal ischemia and necrosis with subsequent bacterial colonization. Acute acalculous cholecystitis represents another organ failure in critically ill patients who are experiencing progressive failure of multiple organ systems. An aggressive approach to the manifestations of organ failure, including acalculous cholecystitis, must be employed.
Drugs purchased by a random sample (17 000) of the population of Jämtland county, Sweden, are continuously monitored. Patients who had been admitted to the county's only hospital with acute cholecystitis and who were part of this sample were studied, and controls matched for age and sex were drawn from the sample. The purchase of thiazides and other drugs prescribed to the patients with acute cholecystitis was compared with that of the controls. The estimated relative risk of developing acute cholecystitis in patients who had purchased thiazides in the year before admission to hospital, as compared with those who had not, was 2.1 (95% confidence limit 1.1-3.9). As it has been reliably reported that the use of thiazides is not itself associated with cholelithiasis, the association found between thiazides and cholecystitis suggests that thiazides may increase the risk of acute cholecystitis developing in a patient with gall stones.
. A daily oral dose of 30 μg of ethynyl oestradiol was taken for 7 days by thirteen healthy young men. Bile was obtained by duodenal aspiration before and after treatment. The cholesterol saturation index of the bile was significantly greater after treatment due to an increase in the molar percentage of cholesterol and phospholipid and a decrease in the molar percentage of total bile acids. The oestrogen had no effect on cholic, deoxycholic and chenodeoxycholic acids expressed as a percentage of the total bile acids, and no change occurred in serum cholesterol. However, there was a significant decrease in serum testosterone concentration at the end of the treatment.
The prevalence of cholesterol gall stones in young women has increased since the introduction of oral contraceptives. The synthetic female sex hormones used in these preparations, increase the degree of cholesterol saturation in bile. To determine whether oestrogens, progestagens, or both, are responsible for the change in biliary cholesterol saturation index, a prospective randomised, controlled study was performed. A significant increase in the cholesterol saturation index of bile was observed when either 30 micrograms ethinyloestradiol plus 150 micrograms norgestrel (p = 0.01) or 50 micrograms ethinyloestradiol plus 250 micrograms norgestrel (p less than 0.01) were ingested daily for two months. No change in the cholesterol saturation index was observed when 30 micrograms ethinyloestradiol alone, or 30 micrograms ethinyloestradiol plus 2.5 mg norethisterone were used. The mechanism for the increase in cholesterol saturation index did not appear to involve bile acid metabolism. These results indicate that the progestagen, norgestrel, and not as previously thought the oestrogen, ethinyloestradiol, is responsible for the increase in cholesterol saturation of bile which accompanies the use of oral contraceptives.