Severe Hepatic Disorders Research Articles

Identification of novel ABCB4 variants and genotype-phenotype correlation in progressive familial intrahepatic cholestasis type 3

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe hepatic disorder characterized by cholestasis. Elucidating the genotype-phenotype correlations and expanding the mutational spectrum of the ABCB4 gene are crucial for enhancing diagnostic accuracy and therapeutic strategies.Clinical and genetic data from 2 original PFIC3 patients from our institution, along with 118 additional cases identified through a comprehensive literature review, were integrated for a comprehensive analysis. The study included statistical analysis of clinical information, genetic analysis, multi-species sequence alignment, protein structure modeling, and pathogenicity assessment. Machine learning techniques were applied to identify genotype-phenotype relationships. We identified three novel ABCB4 mutations: two missense mutations (c.904G > T and c.2493G > C) and one splicing mutation (c.1230 + 1G > A). Homozygous mutations were associated with significantly earlier disease onset compared to compound heterozygous mutations (p < 0.0001). Missense mutations were predominant (76.9%), with Exon 7 being the most frequently affected region. A random forest model indicated that Exon 10 had the highest feature importance score (9.9%). Liver transplantation remains the most effective treatment modality for PFIC3. This investigation broadens the known mutation spectrum of the ABCB4 gene and identifies key variant sites associated with clinical manifestations. These insights lay a foundation for early diagnosis, optimal treatment selection, and further research into PFIC3.

Evaluation of tolvaptan-associated hepatic disorder using different national pharmacovigilance databases

Tolvaptan-associated hepatic disorder is a rare, but lethal adverse event; however, the precise risk and time of onset remain unclear. This study aimed to characterize the severity, time‑to‑onset, and outcomes of hepatic disorder based on patient age and sex. Patient data were acquired from the Japanese Adverse Drug Event Report database (JADER) and the JAPIC AERS database, which consists of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) processed by the Japan Pharmaceutical Information Center. Hepatic disorder was classified as severe or nonsevere. Tolvaptan use was associated with hepatic disorder in analyses using the FAERS [Severe hepatic disorder: reporting odds ratio (ROR) 4.93, 95% confidence interval (CI) 4.33‒5.61; information component (IC) 2.11, 95% CI 1.92‒2.29; nonsevere hepatic disorder: ROR 6.78, 95% CI 6.01‒7.65; IC 2.51, 95% CI 2.33‒2.68] and the JADER (severe hepatic disorder: ROR 4.21, 95% CI 3.57‒4.97; IC 1.86, 95% CI 1.63‒2.10; nonsevere hepatic disorder: ROR 4.27, 95% CI 3.68‒4.95; IC 1.83, 95% CI 1.62‒2.04). A time‑to‑onset analysis revealed that the median onset time was significantly longer in patients aged < 60 years compared with patients aged ≥ 60, regardless of the severity (FAERS: severe hepatic disorder 7 vs. 58 days, p < 0.0001; nonsevere hepatic disorder 8 vs. 52.5 days, p < 0.0001; JADER: severe hepatic disorder 9.5 vs. 32 days, p = 0.0017; nonsevere hepatic disorder 9 vs. 89 days, p < 0.0001). Severe outcomes were observed, regardless of the severity of hepatic disorder. Patients should be monitored for liver function based on age to prevent fatal outcomes.

Role of phlebotomy in the treatment of liver damage related to erythropoietic porphyria

Liver damage affects the prognosis of patients with erythropoietic protoporphyria (EPP). However, there is no radical cure for EPP patients with severe liver damage. This study aims to investigate the effectiveness of phlebotomy in patients with severe liver damage. We examined seven patients diagnosed with EPP and liver damage between 2010 and 2020. Of the 7 cases, phlebotomy was performed in 3 cases with severe hepatic disorder, and the improvement effect of hepatic disorder was observed in all cases. In addition, as an additional study, we also investigated the mechanism by which liver damage becomes more severe. Liver biopsy samples were stained with hematoxylin and eosin and immunohistochemistry was used to examine the expression of adenosine triphosphate-binding transporter G2 (ABCG2). Liver biopsies were performed in 3 of 7 patients with EPP. Of these three patients, ABCG2 expression was low in two patients, especially in the protoporphyrin (PP) deposition area. Two patients with reduced ABCG2 expression subsequently developed severe liver damage. However, the causal relationship between the decreased expression of ABCG2 and the exacerbation of liver damage has not been directly proved, and further investigation is required in the future. This study demonstrated the effectiveness of phlebotomy in EPP patients with severe liver damage.

Safety and efficacy of pediatric liver transplantation in Saudi Arabia

Evidence shows that liver transplantation is a good management choice for pediatric patients with severe hepatic disorders. In addition, the approach can be used for managing different hepatic disorders, including metabolic and familial ones. Therefore, liver transplantation is indicated and should be urgently conducted to intervene against further deterioration in the health status of the affected patients and enhance their prognosis. Various investigations in the literature validated the efficacy of the modality for different age groups, although many of them reported the incidence of different related complications. In Saudi Arabia, not many studies reported the safety and efficacy of liver transplantation for pediatric patients. The present literature review provided insight regarding the safety and efficacy of the procedure for this population group. We can conclude that liver transplantation in pediatric settings is a safe and productive approach that can be successfully conducted with a favorable prognosis. Moreover, it has been shown that living-related liver transplantation is more favorable than cadaveric-related liver transplantation in these settings, especially when there is a graft shortage, as reported in Saudi Arabia. Despite the favorable outcomes, further reports are still needed for validating the current evidence.

Four-And-A-Half LIM-Domain Protein 2 (FHL2) Deficiency Aggravates Cholestatic Liver Injury.

Cholestasis occurs in different clinical circumstances and leads to severe hepatic disorders. The four-and-a-half LIM-domain protein 2 (FHL2) is a scaffolding protein that modulates multiple signal transduction pathways in a tissue- and cell context-specific manner. In this study, we aimed to gain insight into the function of FHL2 in cholestatic liver injury. FHL2 expression was significantly increased in the bile duct ligation (BDL) model in mice. In Fhl2-deficient (Fhl2-ko) mice, BDL caused a more severe portal and parenchymal inflammation, extended portal fibrosis, higher serum transaminase levels, and higher pro-inflammatory and pro-fibrogenic gene expression compared to wild type (wt) mice. FHL2 depletion in HepG2 cells with siRNA resulted in a higher expression of the bile acid transporter Na+-taurocholate cotransporting polypeptide (NTCP) gene. Furthermore, FHL2-depleted HepG2 cells showed higher expression of markers for oxidative stress, lower B-cell lymphoma 2 (Bcl2) expression, and higher Bcl2-associated X protein (BAX) expression after stimulation with deoxycholic acid (DCA). In hepatic stellate cells (HSCs), FHL2 depletion caused an increased expression of TGF-β and several pro-fibrogenic matrix metalloproteinases. In summary, our study shows that deficiency in FHL2 aggravates cholestatic liver injury and suggests FHL2-mediated effects on bile acid metabolisms and HSCs as potential mechanisms for pronounced hepatocellular injury and fibrosis.

PF764 PRETRANSPLANT INCREASING RATE OF LACTATE HYDROGENASE DURING TREATMENT FREE PERIOD PREDICTS TRANSPLANT OUTCOMES FOR PATIENTS WITH MYELOID HEMATOLOGICAL MALIGNANCIES NOT IN REMISSION

Background:For patients (pts) with refractory myeloid hematological malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), allogeneic stem cell transplantation (allo‐SCT) is essential for cure. The long‐term outcomes for pts not in remission is previously reported as poor as 10–30% after allo‐SCT. There are several reports that pretransplant blast ratios in both bone marrow and peripheral blood are predictive markers for outcomes. Since the tumor growth of some pts with non‐complete remission (CR) status are indolent, these pts might not be evaluated accurately only by blast ratios and the assessment of tumor proliferation rates may be needed.Aims:For the purpose of the assessment of tumor proliferation, we evaluated the impact of pretransplant increasing rates of lactate hydrogenase (LDH) during treatment free period on long‐term transplant outcomes.Methods:Among 283 pts with AML or MDS who underwent allo‐SCT at our institute from 2009 to 2018, 74 pts with non‐CR status were candidates for this retrospective study. Pts with severe hepatic disorder (CTCAE grade≥3) or with their second transplant were excluded and 67 pts were eligible. We evaluated changes of patients’ LDH for 12 days (±2 days) during the latest treatment free period before conditioning therapies for allo‐SCT. Treatment free period was defined as interval of 2 weeks or more from the previous chemotherapy. Pts with no previous chemotherapies were also included.The primary endpoint of this study was to evaluate the long‐term outcome of overall survival (OS).Results:Median patient age was 53 years (17–68). The risks of diseases were intermediate in 48 and high in 19 pts. Twenty‐three pts were diagnosed of AML, 32 pts of AML with myelodysplasia‐related changes and 12 pts of MDS. Transplant donor sources were as follows: bone marrow, 42 pts; peripheral blood, 16 pts; cord blood, 9 pts.With a median follow up period of 45.9Mo, the probability of OS at 36‐months after allo‐SCT was 37.3% (95%CI, 25.4–49.2). Univariate log rank analyses showed that variables of higher increased rate of LDH (36‐months OS = 9.1%, 95%CI, 1.9–23.6, P &lt; 0.01), absolute LDH value at conditioning chemotherapy (36‐months OS = 22.8%, 95%CI, 9.3–39.7, P = 0.029) and chemotherapy performed before treatment free period (36‐months OS = 25.0%, 95%CI, 10.9–42.0, P = 0.028) were significantly associated with poor OS. But higher blast ratio was not (36‐months OS = 29.3%, 95%CI, 15.0–45.1, P = 0.40). High disease risk index was correlated with poor OS but not significant (36‐months OS = 25.3%, 95%CI, 8.6–46.2, P = 0.051). In multivariate Cox proportional‐hazards regression models, a variable of higher increased rate of LDH only remained associated with poor OS (HR = 4.38, 95%CI, 1.73–11.08, P &lt; 0.01).Summary/Conclusion:Pretransplant higher increased rate of LDH significantly predicted poor OS. Comparing to previously reported variables of blast ratio and disease risk index, higher increased rate of LDH was the solely strongest predictive marker for the long‐term outcome. We conclude that our novel assessment of tumor proliferation by evaluating pretransplant increasing LDH rates during treatment free period predicts poor long‐term transplant outcomes for patients with myeloid hematological malignancies not in remission.image

Revisiting Epithelial-to-Mesenchymal Transition in Liver Fibrosis: Clues for a Better Understanding of the "Reactive" Biliary Epithelial Phenotype.

Whether liver epithelial cells contribute to the development of hepatic scarring by undergoing epithelial-to-mesenchymal transition (EMT) is a controversial issue. Herein, we revisit the concept of EMT in cholangiopathies, a group of severe hepatic disorders primarily targeting the bile duct epithelial cell (cholangiocyte), leading to progressive portal fibrosis, the main determinant of liver disease progression. Unfortunately, therapies able to halt this process are currently lacking. In cholangiopathies, fibrogenesis is part of ductular reaction, a reparative complex involving epithelial, mesenchymal, and inflammatory cells. Ductular reactive cells (DRC) are cholangiocytes derived from the activation of the hepatic progenitor cell compartment. These cells are arranged into irregular strings and express a “reactive” phenotype, which enables them to extensively crosstalk with the other components of ductular reaction. We will first discuss EMT in liver morphogenesis and then highlight how some of these developmental programs are partly reactivated in DRC. Evidence for “bona fide” EMT changes in cholangiocytes is lacking, but expression of some mesenchymal markers represents a fundamental repair mechanism in response to chronic biliary damage with potential harmful fibrogenetic effects. Understanding microenvironmental cues and signaling perturbations promoting these changes in DRC may help to identify potential targets for new antifibrotic therapies in cholangiopathies.

Role of Toll-Like Receptors in Hepatitis C Virus Pathogenesis and Treatment.

Viral infections are rising every day, and viruses appear to be the most dangerous pathogens in the world. Hepatitis C virus (HCV) is accepted as one of the major destructive factors of promoting severe hepatic disorders by infecting more than 180 million individuals throughout the world. Chronic infection caused by HCV poses a serious global health emergency and appears to be a powerful threat to humanity. Almost 20 years have passed since the disclosure of HCV, but even now, treatment preferences remain limited. Humans are born with a rapid and nonspecific mechanism to prevent viral attacks through Toll-like receptors (TLRs), which are evolutionary conserved cellular activator proteins responsible for recognizing specific components present on penetrating microbes and viruses. Recent research efforts in TLR biology suggest that targeting the TLRs and their signaling pathways during HCV infection could contribute to novel therapies against HCV. The mobilization of TLRs boosts antiviral communication and integrates the development of long-lasting acquired immune responses to limit viral pathogenesis. Both activation and suppression of TLRs are necessary for the efficient treatment of HCV. For the proper management and eradication of HCV, novel drugs that target TLRs and their signaling pathway are needed. This review summarizes the role of TLR signaling in HCV infection and treatment.

THE IMPACT OF CLINICAL PHARMACIST MANAGED ANTICOAGULATION MANAGEMENT SERVICE VERSUS ROUTINE MEDICAL CARE ON THE CLINICAL OUTCOME OF ATRIAL FIBRILLATION PATIENTS: AN EGYPTIAN PILOT STUDY.

Aim. To assess impact of pharmacist managed anticoagulation management service on Egyptian atrial fibrillation patients’ anticoagulation management, incidence and severity of bleeding events and thromboembolic events, incidence of warfarin drug and food interactions. Methods. Prospective, randomized, controlled study. Patients presenting to Cardiology Department, Ain Shams University Hospitals, Cairo, from November 2012 to February 2014, were assessed for eligibility. Inclusion criteria; newly diagnosed AF patients who would receive anticoagulation with warfarin, aged 18- 80 years, moderate to high risk of developing stroke. Exclusion criteria; patient with renal disorder or on renal dialysis, pregnancy or lactation, dementia, moderate to severe hepatic disorder, valvular heart disease, clinically significant active bleeding, recurrent DVT or PE. Patients were randomly assigned to; control (routine medical care group); 30 atrial fibrillation patients subjected to regular care, or study (pharmacist group); 30 atrial fibrillation patients subjected to pharmacist managed anticoagulation management service. For both groups; demographics, anticoagulation knowledge assessment questionnaire (AKA) and INR were assessed initially and patients given a side effect self-reporting card. Study group was subjected to a systematic anticoagulation management and education. Follow up was done continuously for 6 months for both groups and final evaluation included; percentage time in therapeutic range (TTR), anticoagulation knowledge assessment questionnaire (AKA), side effect, warfarin drug and food interaction reporting.

MBSJ MCC Young Scientist Award 2012 Liver regeneration: a unique and flexible reaction depending on the type of injury.

The liver can be thought of as a mysterious organ, because it has an elegant regenerative capability. This phenomenon has been well known since ancient times and is already applied to medical treatments for severe hepatic disorders by transplanting portions of liver received from living donors. However, it was not until quite recently that the mechanism underlying the principle of liver regeneration was investigated more deeply. Recent advances in the technologies for characterizing cell properties and examining the molecular nature of cells are enabling us to understand what occurs in the regenerating liver. After acute liver damage, hepatocytes actively proliferate in response to external stimulation by humoral factors. However, in the chronically injured liver, hepatocytes cannot proliferate well, but biliary cells appearing after chronic liver damage form primitive ductules around portal veins of the liver. These biliary cells may have a multiple origin, including hepatocytes, and contain progenitor cells giving rise to both hepatocytes and biliary cells, or represent cells that can be directly converted into hepatocytes. Although liver regeneration is more complicated than we had thought, unremitting efforts by researchers will certainly connect the numerous findings obtained in basic research with the development of new therapeutic strategies for liver diseases.

Identification of genetic loci affecting the establishment and development of Echinococcus multilocularis larvae in mice

Alveolar echinococcosis (AE) is a severe hepatic disorder caused by larval infection by the fox tapeworm Echinococcus multilocularis. The course of parasitic development and host reactions are known to vary significantly among host species, and even among different inbred strains of mice. As reported previously, after oral administration of parasite eggs, DBA/2 (D2) mice showed a higher rate of cyst establishment and more advanced protoscolex development in the liver than C57BL/6 (B6) mice. These findings strongly suggest that the outcome of AE is affected by host genetic factor(s). In the present study, the genetic basis of such strain-specific differences in susceptibility/resistance to AE in murine models was studied by whole-genome scanning for quantitative trait loci (QTLs) using a backcross of (B6 × D2)F 1 and D2 mice with varying susceptibility to E. multilocularis infection. For cyst establishment, genome linkage analysis identified one suggestive and one significant QTL on chromosomes (Chrs.) 9 and 6, respectively, whereas for protoscolex development, two suggestive and one highly significant QTLs were detected on Chrs. 6, 17 and 1, respectively. Our QTL analyses using murine AE models revealed that multiple genetic factors regulated host susceptibility/resistance to E. multilocularis infection. Moreover, our findings show that establishment of the parasite cysts in the liver is affected by QTLs that are distinct from those associated with the subsequent protoscolex development of the parasite, indicating that different host factors are involved in the host–parasite interplay at each developmental stage of the larval parasite. Further identification of responsible genes located on the identified QTLs could lead to the development of effective disease prevention and control strategies, including an intensive screening and clinical follow-up of genetically high-risk groups for AE infection.

Novel photodynamic therapy against biliary tract carcinoma using mono‐l‐aspartyl chlorine e6: basic evaluation for its feasibility and efficacy

Recently, a second-generation photosensory agent for photodynamic therapy (PDT), mono-L: -aspartyl chlorine e6 (NPe6), which degrades rapidly in vivo, has been developed. We evaluated its feasibility and efficacy for treatment in biliary tract carcinoma. A transmittance of semiconductor laser light (664 nm), sensitivity of a human biliary tract carcinoma cell line, and disorder to normal tissue including Glissonian constructs and adjacent hepatocytes were investigated. The transmittance of the laser was 85-91% through yellow clear bile and that of the bile including 50 microg/ml NPe6 was 17-48%. The effective concentration of NPe6 which showed LD50 for a cell line was 12.5 microg/ml, and that of LD95 was 25 microg/ml. NPe6 in the supernatant reduced laser transmissiveness, but it had little influence on the antitumor effect in supernatant with or without NPe6. The NOZ cell-tumor volume was reduced significantly 14 days after irradiation in the PDT group (PDT 69.9 +/- 44.6 mm(3) vs control 296.3 +/- 239.9 mm(3) P < 0.05). No severe hepatic disorder including Glisson components was observed by the histological findings. NPe6 PDT was effective in carcinomas even in the presence of bile, and causes no serious complication for the liver and Glisson structure. Therefore, NPe6 PDT will be a useful candidate as a new therapy for biliary tract carcinomas.

High frequency of Human Cytomegalovirus DNA in the Liver of Infants with Extrahepatic Neonatal Cholestasis

BackgroundBiliary atresia (BA) is the most severe hepatic disorder in newborns and its etiopathogenesis remains unknown. Viral involvement has been proposed, including the human cytomegalovirus (HCMV). The aims of the study were to use the polymerase chain reaction (PCR) to screen the liver tissue of infants with extrahepatic cholestasis for HCMV and to correlate the results with serological antibodies against HCMV and histological findings.MethodsA retrospective study in a tertiary care setting included 35 patients (31 BA, 1 BA associated with a choledochal cyst, 2 congenital stenosis of the distal common bile duct and 1 hepatic cyst). HCMV serology was determined by ELISA. Liver and porta hepatis were examined histologically. Liver samples from infants and a control group were screened for HCMV DNA.ResultsTwelve patients had HCMV negative serology, 9 were positive for IgG antibodies and 14 were positive for IgG and IgM. Nine liver and seven porta hepatis samples were positive for HCMV DNA but none of the control group were positive (general frequency of positivity was 34.3% – 12/35). There was no correlation between HCMV positivity by PCR and the histological findings. The accuracy of serology for detecting HCMV antibodies was low.ConclusionThese results indicate an elevated frequency of HCMV in pediatric patients with extrahepatic neonatal cholestasis. They also show the low accuracy of serological tests for detecting active HCMV infection and the lack of correlation between HCMV positivity by PCR and the histopathological changes.

Bile and Blood Ratios of Cyclosporin and its Metabolites in Patients on Continuous Infusion During the First Three Weeks after Liver Transplantation

Ten patients with orthotopic liver transplants were investigated during routine therapeutic monitoring to study the relationship between the concentrations of cyclosporin and its metabolites in blood, bile and urine, and whether this information can provide early signs of severe hepatic disorders post-transplantation. Cyclosporin (Sandimmun®) was administered by continuous infusion at a constant rate of 5 mg/kg/day, modified to keep the blood cyclosporin concentration within the target range (400 to 500 μg/L). The concentrations of cyclosporin and combined cyclosporin-metabolites in blood, bile and urine were assayed daily during the 3 post-transplantation weeks that the patients spent in intensive care.All patients developed cholestatis and cytolysis during the first week. The severity of these liver transplant disorders increased in 5 patients and decreased in the other 5 in the second week. The pharmacokinetics of cyclosporin differed in the 2 groups: in patients without severe hepatic disorders, the blood metabolites/cyclosporin ratio (M/C) stabilised at 1.2 ± 0.4 in week 2 and at 0.8 ± 0.2 in week 3, bile cyclosporin/blood cyclosporin (bile C/blood C) fluctuated around 13.5 (13.5 ± 9.5 in week 2 and 13.5 ± 9.0 in week 3) and the bile metabolite/blood metabolite (bile M/blood M) ratio was very high and variable (131 ± 86 in week 2 and 159 ± 116 in week 3). Metabolites significantly accumulated in the blood of patients with severe hepatic disorders (M/C = 2.8 ± 0.6 in week 2 and 3.5 ± 1.0 in week 3); bile C/blood C (2.6 ± 2.1 in week 2 and 3.4 ± 1.1 in week 3) and bile M/blood M (11.9 ± 7.8 in week 2 and 12.5 ± 7.9 in week 3) significantly decreased and showed less interindividual variability.Blood cyclosporin is usually monitored to help optimise the dosage. However, if this was extended to include the monitoring of metabolites in the blood, and cyclosporin and metabolites in the bile, it could provide an early indication of severe hepatic disorders in patients with transplanted livers.

A case of the adult crisis Still's disease complicated by severe hepatic disorder and disseminated intravascular coagulation (DIC).

A case of the adult crisis Still's disease complicated by severe hepatic disorder and disseminated intravascular coagulation (DIC).

Changes in hepatic lipid composition after infection by LP-BM5 murine leukemia virus causing murine aids

The severe hepatic disorders in patients with acquired immune deficiency syndrome (AIDS) is often attributed to a variety of other factors which could affect hepatic function. To evaluate the mechanism of liver damage in murine AIDS-induced immune-suppressed animal, a murine model of AIDS (MAIDS), caused by infection with LP-BM5 murine leukemia virus was used at a late stage of the disease. Retroviral infection significantly increased hepatic cholesterol, triacylgycerol and the cholesterol/phospholipid ratio. Similarly, the proportions of palmitic, palmitoleic, linoleic, ratios of linoleic to arachidonic and saturated to unsaturated fatty acids were significantly lower while the proportion of oleic, docosatetraenoic and docosahexenoic fatty acids were significantly increased in the retrovirus infected mice. Hepatic dysfunction as evidenced by increased serum transaminase levels were also observed in the retrovirus infected animals. The data suggest that the liver damage in murine AIDS is induced by retroviral infection and the desaturase enzymes system necessary to maintain regular balance of the fatty acids in the cells may be affected during retroviral infection.

Two cases of severe hepatic disorder by acetaminophen.

Two cases of severe hepatic disorder by acetaminophen.

DC89-A1, a new antitumor antibiotic from Streptomyces.

The effectiveness and safety of cefmenoxime (CMX) in the treatment of respiratory tract infections were evaluated, mainly in relation to the appearance of hemorrhagic tendency. Out of 80 patients treated in this study, 57 were treated with CMX alone, and an effective rate was determined to be 75.4%. As for a tendency toward hemorrhage, none of the patients clinically exhibited a hemorrhagic tendency, while the prolongation of prothrombin time (PT) and/or activated partial thromboplastin time (APTT) was seen in 3 patients (3.8%), who were all at ages over 63. The prolongation of APTT was clearly related to CMX in 1 patient. Although the causal relation between CMX and the prolongation of PT or APTT was unclear in the remaining 2 patients because they had severe primary diseases (lung cancer and respiratory failure due to chronic obstructive lung disease in addition to severe hepatic disorder and received combination treatment with anticancer agents or other antibiotics), CMX might have a role in causing these phenomena. Even though none of the patients showed a hemorrhagic tendency clinically arousing problems, we should be careful in using CMX in the treatment of the aged and patients in poor general conditions because PT and/or APTT was observed to prolong with the use of CMX in some patients.

Factors influencing the caffeine test for cytochrome P 448-dependent liver function.

Liver functions in patients with liver disease can be estimated by caffeine clearance. Our data, however, demonstrate the additional influence of factors other than liver disease on the caffeine test. Smoking enhances caffeine clearance in both healthy volunteers and patients with severe hepatic disorders, whereas co-medication with mexiletine strongly inhibits caffeine elimination.

Fecal chymotrypsin levels in children with pancreatic insufficiency

The fecal chymotrypsin (FC) levels in samples collected over 24 h were determined by a new commercial colorimetric method from Boehringer Mannheim in 82 children suffering from various pancreatic disorders. The patients were divided into 4 groups, in accordance with the following etiologies: cystic fibrosis of the pancreas (CFP), chronic severe hepatic disorders (CSH), primary malabsorption syndrome (PMS) and malnutrition due to nondigestive causes (M). The control group comprised 48 children of similar ages. The 24th FC levels as U/g (mean +/- SD) were: 34 +/- 6 in the control group, 2 +/- 2 in the CFP group, 15 +/- 6 in the M group, 19 +/- 9 in the CSH group and 43 +/- 13 in the PMS group. The differences between the CFP patients and all the other groups were statistically significant. These results indicate that the FC levels may be suitable as a diagnostic indication of CFP and capable of differentiating between this disorder and other causes of pancreatic insufficiency.