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Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by the development of arteriovenous malformations (AVMs) that can result in significant morbidity and mortality. HHT is caused primarily by mutations in bone morphogenetic protein receptors ACVRL1/ALK1, a signaling receptor, or endoglin (ENG), an accessory receptor. Because overexpression of Acvrl1 prevents AVM development in both Acvrl1 and Eng null mice, enhancing ACVRL1 expression may be a promising approach to development of targeted therapies for HHT. Therefore, we sought to understand the molecular mechanism of ACVRL1 regulation. We previously demonstrated in zebrafish embryos that acvrl1 is predominantly expressed in arterial endothelial cells and that expression requires blood flow. Here, we document that flow dependence exhibits regional heterogeneity and that acvrl1 expression is rapidly restored after reinitiation of flow. Furthermore, we find that acvrl1 expression is significantly decreased in mutants that lack the circulating Alk1 ligand, Bmp10, and that, in the absence of flow, intravascular injection of BMP10 or the related ligand, BMP9, restores acvrl1 expression in an Alk1-dependent manner. Using a transgenic acvrl1:egfp reporter line, we find that flow and Bmp10 regulate acvrl1 at the level of transcription. Finally, we observe similar ALK1 ligand-dependent increases in ACVRL1 in human endothelial cells subjected to shear stress. These data suggest that ligand-dependent Alk1 activity acts downstream of blood flow to maintain or enhance acvrl1 expression via a positive feedback mechanism, and that ALK1 activating therapeutics may have dual functionality by increasing both ALK1 signaling flux and ACVRL1 expression., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Blood flow plays crucial roles in vascular development, remodeling and homeostasis, but the molecular pathways required for transducing flow signals are not well understood. In zebrafish embryos, arterial expression of activin receptor-like kinase 1 (alk1), which encodes a TGFβ family type I receptor, is dependent on blood flow, and loss of alk1 mimics lack of blood flow in terms of dysregulation of a subset of flow-responsive arterial genes and increased arterial endothelial cell number. These data suggest that blood flow activates Alk1 signaling to promote a flow-responsive gene expression program that limits nascent arterial caliber. Here, we demonstrate that restoration of endothelial alk1 expression to flow-deprived arteries fails to rescue Alk1 activity or normalize arterial endothelial cell gene expression or number, implying that blood flow may play an additional role in Alk1 signaling independent of alk1 induction. To this end, we define cardiac-derived Bmp10 as the crucial ligand for endothelial Alk1 in embryonic vascular development, and provide evidence that circulating Bmp10 acts through endothelial Alk1 to limit endothelial cell number in and thereby stabilize the caliber of nascent arteries. Thus, blood flow promotes Alk1 activity by concomitantly inducing alk1 expression and distributing Bmp10, thereby reinforcing this signaling pathway, which functions to limit arterial caliber at the onset of flow. Because mutations in ALK1 cause arteriovenous malformations (AVMs), our findings suggest that an impaired flow response initiates AVM development.

The carpal tunnel is most narrow at the level of the hook of the hamate. The median nerve is the most superficial structure. It has specific relationships to surrounding structures within the carpal tunnel to the ulnar bursa, flexor tendons, and endoscopic devices placed inside the canal. The importance of the ring finger axis is stressed. Knowledge of topographical landmarks that mark the borders of the carpal tunnel, the hook of the hamate, superficial arch, and thenar branch of the median nerve ensure appropriate incision placement for endoscopic as well as open carpal tunnel release surgery. Anatomy of the transverse carpal ligament, its layers and relationships to adjacent structures including the fad pad, Guyon's canal, palmar fascia, and thenar muscles has been discussed. Fibers derived primarily from thenar muscle fascia with connections to the hypothenar muscle fascia and dorsal fascia of the palmaris brevis form a separate fascial layer directly palmar to the TCL and can be retained. This helps to preserve postoperative pinch strength. The fat pad in line with the ring finger axis overlaps the deep surface of the distal edge of the TCL and must be retracted in order to visualize the distal end of the ligament. Whereas the ulnar artery within Guyon's canal is frequently located radial to the hook of the hamate, injury to this structure has not been a problem during ECTR surgery. Variations of the median nerve and its branches, as well as the palmar cutaneous nerve distribution, have been reviewed. A rare ulnar-sided thenar branch from the median nerve, interconnecting branches between the ulnar and median nerves located just distal to the end of the TCL, and transverse ulnar-based cutaneous nerves can be injured during open or ECTR surgery. Anomalous muscles, tendons or interconnections, and the lumbricals during finger flexion may be seen within the carpal tunnel. These structures can be the cause of compression of the median nerve. The anatomy of the carpal tunnel and surrounding structures have been reviewed with emphasis on clinical applications to endoscopic and open carpal tunnel surgery. A thorough knowledge of the anatomy of the carpal tunnel is essential in order to avoid complications and to ensure optimal patient outcome. An understanding of the contents and their positions and relationships to each other allows the surgeon to perform a correct approach and accurately identify structures during procedures at or near the carpal tunnel.

The endoscopic evaluation of the asymptomatic liver transplant patient is essential to risk-stratify the patient for future complications related to portal hypertensive bleeding (i.e., presence of large varices), and to exclude findings (e.g., malignancy) that might preclude the patient from consideration of OLT. Because waiting times for transplant are longer after listing, preventive management becomes imperative to diminish attrition on the waiting list and maintain long-term success. Following OLT, endoscopy may be performed to assess a number of common problems: gastrointestinal blood loss that may be caused by anastomotic lesions; persistent portal hypertensive bleeding; biliary complications, including leaks and strictures; and systemic processes (e.g., infectious diseases or lymphoproliferative disorder (LPD). Clearly, endoscopy plays an integral role in the successful management of the patient before and after OLT.

Purpose: To report our results of medical management of myopia, and add these to the prior literature supporting this practice., Method: Retrospective review of the medical records of 35 patient-subjects offered this treatment with adequate followup over a five year period. Treatment consisted of prescription of photochromic gray extra lenses incorporating full myopic correction with a +3.00 bifocal addition, and atropine 1% ophthalmic drops, one in each eye, each night at bedtime. Compliance was monitored based upon mydriasis and cycloplegia., Results: The mean change in refractive error per year was +0.07 diopters for the always compliant group, that is, a decrease in the amount of myopia; -0.18 diopters per year for the sometimes compliant group; and -0.17 diopters for the never compliant group, an increase in the degree of myopia. Statistical comparison of our always compliant group with each of the other two groups using the t-test, yielded a P value of P<.10 in each case, considered to be "medically/clinically significant". Comparison of the mean annual change in refractive error of our always compliant group (+0.07 D/yr) with the mean annual change in re-fractive error in the general population aged 8-15 years (-0.24 D/yr) shows an absolute difference of 0.31 D/yr. This difference is "statistically significant" (t-test) with a P <.02., Conclusion: Atropine and bifocals are an appropriate, effective, and safe management for progressive school myopia; and probably also for pathological myopia.

CA125 is the most widely used tumor marker presently available for use in patients with epithelial ovarian cancer. Although elevated in a high percentage of patients with ovarian cancer, serum CA125 levels have also been detected in patients with numerous benign and malignant nongynecologic disorders, including various diseases of the liver. Despite this well-publicized fact, it has become apparent that the association between CA125 elevation, particularly the degree of elevation, and liver disease may not be as widely recognized as one would suspect. When marked CA125 elevations occur, diagnostic confusion is common. We describe two cases illustrative of this point. Both cases involve middle-aged women who presented with massive ascites and due to markedly elevated serum CA125 levels underwent exploratory laparotomy with hysterectomy and/or bilateral salpingo-oopherectomy before their referral to our center. Because preservation of a woman's reproductive organs is a significant concern, it is imperative that both primary care physicians and specialists are aware of such associations and the proper use of tumor markers.

Background: Cerebral oedema is a cause of morbidity and mortality in fulminant hepatic failure but has not been well documented as a complication of chronic liver diseases. We report here the development of cerebral oedema and increased intracranial pressure in 12 patients with chronic liver disease., Methods: Between July 1, 1987, and Dec 31, 1993, we studied 12 patients aged 29-67 years with end-stage chronic liver disease. All the patients had cirrhosis, portal hypertension, hypoprothrombinaemia, hepatic encephalopathy, and decreased serum concentrations of albumin (<25 g/L). During the study, the patients developed signs of increased intracranial pressure and had documented intracranial hypertension, cerebral oedema, or both. Intracranial hypertension was suspected on physical examination and confirmed by epidural catheters. We detected cerebral oedema by computed axial tomography of the head and necropsy of the brain when possible., Findings: All the patients had intracranial hypertension and cerebral oedema. Two patients had successful treatment of cerebral hypertension with improvement of intracranial pressure such that orthotopic liver transplantation was undertaken. Both patients became neurologically normal after transplantation. Eight patients had only a transient response to treatment and died of cerebral oedema before a transplant could be done., Interpretation: Cerebral oedema and increased intracranial pressure can occur in chronic liver disease and presents as neurological deterioration. Treatment guided by monitoring of intracranial pressure can lead to the reversal of intracranial hypertension, but in most patients cerebral oedema contributes to death or places them at too high a risk for liver transplantation.

A multicenter, retrospective analysis of 623 liver transplant recipients was performed to define safe and effective cyclosporine doses and blood levels at various times after transplantation. Patient and graft survival were assessed as efficacy parameters, and serum creatinine and cholesterol levels as safety parameters. The mean daily cyclosporine dose was 12.1 mg/kg/d at 1 month posttransplantation and 5.5 mg/kg/d after 1 year. After 4 years, the mean cyclosporine dose was maintained at 4.0 mg/kg/d. Mean cyclosporine blood levels showed a similar trend. Patient and graft survival after 4 years of cyclosporine maintenance therapy were 72% and 67%, respectively. Both serum creatinine and cholesterol levels were stable over the study period, and neither correlated with cyclosporine dose. The cumulative incidence of biopsy-proven acute cellular rejection was 59% for early (< 6 months) episodes and 21% for late (> or = 6 months) episodes. Patient and graft survival did not differ significantly between patients experiencing early or late acute rejection episodes and those who did using univariate analysis. The high patient and graft survival, low rejection rates, and lack of significant renal dysfunction or hypercholesterolemia suggest that the cyclosporine doses and blood levels described are safe and therapeutically effective.

Background: Immunotherapy is a recognized component in the management of allergic rhinitis. Its efficacy has been evaluated in a number of clinical field trials. These methods of evaluation are limited by control of antigen exposure., Objective: A study was designed to evaluate the efficacy of immunotherapy in ragweed-induced rhinoconjunctivitis using an environmental exposure unit., Methods: Forty-three subjects were grouped into (1) immunotherapy group: ragweed-allergic subjects on maintenance ragweed immunotherapy for at least 2 years (N = 16), (2) positive control group: ragweed-allergic subjects who had never received immunotherapy (n = 16), and (3) negative control group: ragweed-nonallergic subjects (N = 11). Ragweed specific skin tests and ragweed IgE levels were obtained prior to exposure. The study was done in a room where levels of 2,500 to 3,000 grains m3 of ragweed were maintained over three hours. Symptoms were recorded every 15 minutes., Results: Nasal symptoms in the immunotherapy group were significantly less than in the positive control group after 45 minutes (P = .025). Significant differences were not observed for ocular symptoms. Combined nasal and ocular scores were 50% less in the immunotherapy group than in the positive control group by 75 minutes (P = .039). Ragweed-specific skin tests and IgE were significantly less in the immunotherapy group than in the positive control group. Rhinoconjunctivitis symptoms in the negative control group were absent throughout., Conclusions: Controlled ragweed pollen exposure in this setting demonstrated that ragweed immunotherapy significantly reduced symptoms of ragweed-allergic rhinitis but had no significant effect on ocular symptoms. This system presents opportunities for additional studies on immunotherapy for allergic respiratory conditions.

It is not well understood whether posttransplant diabetes mellitus (PTDM) following orthotopic liver transplantation (OLTx) alters postoperative morbidity. This study was designed to evaluate this question. All adult patients who received an OLTx between July 1985 and March 1993 (n = 497) were evaluated by retrospective chart review for evidence of PTDM after OLTx. The patients identified with PTDM (n = 26) were case matched with nondiabetic OLTx recipients based on primary liver disease diagnosis, age, gender, date of first OLTx, and survival. Liver synthetic function, number and severity of rejection episodes, graft survival, total number of hospital days within the first year post-OLTx, renal function, and number and type of infection episodes were analyzed to assess differences in morbidity between the PTDM and control patients after OLTx. Of the 497 adult patients who underwent OLTx, 26 (5.2%) were identified as having PTDM within 1 month of discharge. Factors which identified individuals at higher risk for DM after OLTx included higher pre-OLTx fasting blood glucose (P = .04); lower body mass index after OLTx (P = .02); and cyclosporine rather than OKT3 induction (P = .009). Graft survival, synthetic function, and the total number of rejection episodes during the first year were not different between the two groups. The morbidity variables of total number of days in the hospital during the first 12 months, renal function, and type and number of infections were also similar between the two groups. In summary, 5.2% of adult patients developed DM within 1 month of OLTx. Pre-existing insulin resistance, postoperative stress, and immunosuppression medications all likely contribute to the development of overt hyperglycemia after OLTx. Although PTDM can be a consequence of OLTx, it does not have a significant impact on patient outcome in the first year after OLTx.

Although the incidence of spousal transmission of hepatitis C virus (HCV) in chronic carriers is extremely low (1.4% to 8%), hepatitis C recurrence after liver transplantation is common with markedly increased serum HCV RNA levels. Thus, partners of these patients may be at higher risk of acquiring infection. This study evaluates the prevalence of spousal transmission of hepatitis C after liver transplantation. Twenty-two of 25 couples who were eligible agreed to the retrospective study. Twenty-two patients (17 males, 5 females) and spouses (5 males, 17 females) were studied with respective mean ages of 50.2 years (35 to 65 years) and 46.9 years (33 to 66 years). Liver enzymes, second-generation enzyme-linked immunosorbent assay (ELISA) for antibody to HCV (anti-HCV) and HCV RNA by polymerase chain reaction (PCR), and branched DNA assay were performed. HCV-associated antibodies were detected in 1 of 22 (5%) spouses and 21 of 22 (95%) patients (P < .0001). Nineteen of 22 (86%) patients tested positive by PCR with a mean value of 16,218,100 Eq/mL (464,700 to 51,980,000). All spouses including the only ELISA anti-HCV positive spouse tested negative by PCR (P < .0001). Eight of 21 spouses tested negative for anti-HCV pretransplantation, (13 of 21 pretransplantation were not tested). Estimated mean duration of hepatitis C infection in patients was 14 years (3 to 40 years). Mean patient follow-up posttransplantation was 654.5 days (141 to 1,959 days). Mean duration of marriage was 22.6 years (2.5 to 46 years). No risk factors other than exposure to index patients were observed in spouses. The incidence of spousal transmission of HCV in liver transplantation remains low (5%) and similar to chronic carriers of HCV.

BAEPs were recorded on 18 patients before, and/or after liver transplantation. Clinical assessment included 5 standardized scales. Data were divided by stringent criteria into 2 groups: clinical hepatic encephalopathy present (HE) or absent (nonHE). Dependent variables were BAEP configuration and I-V, I-III and III-V IPLs. The following comparisons were made: all patients vs. controls; HE vs. controls; nonHE vs. controls; HE vs. nonHE. BAEP configuration changes were not significantly associated with HE. I-V and III-V IPLs were prolonged for all patients, nonHE patients, and HE patients vs. controls; I-III IPL differences were not significant. There were no correlations between BAEP variables and EEG grade or grades on any single clinical scale. The results suggest that BAEP IPLs (especially the I-V IPL) are a sensitive, although not specific, measure of HE and may be sensitive enough to detect incipient HE.

Liver biopsy is an important diagnostic tool in the management of patients following orthotopic liver transplant. We evaluated complications following percutaneous liver biopsy in a group of liver transplant patients who had Roux-en-Y choledochojejunostomies fashioned as part of their biliary reconstruction during liver transplantation. Complications were divided into two major groups: septic complications (including fever, symptomatic bacteremia, cholangitis, infected hematoma and hypotension related to sepsis) and bleeding (defined as hypotension requiring volume expansion greater than 500 cm3 or blood transfusion, hemothorax, intrahepatic or peritoneal hemorrhage and hemobilia occurring within 1 wk of liver biopsy). One hundred ninety-two biopsies were performed in 46 patients with choledochojejunostomies, and 118 biopsies were carried out in an age- and sex-matched control group of patients with choledochocholedochostomy biliary anastomosis. There were no septic complications in the choledochojejunostomy patients and one (0.32%) septic complication in the choledochocholedochostomy patients (NS). Eight bleeding complications occurred (2.6%) in eight patients (8.3%). Five (2.6%) occurred in five (10.8%) of the choledochojejunostomy patients, vs. three (2.5%) in three (6.5%) choledochocholedochostomy patients (NS). None of the bleeding complications required surgical intervention or was fatal. We conclude that liver biopsy in posttransplant patients with Roux-en-Y choledochojejunostomies is a safe procedure and that the incidences of complications were similar in our two groups. The negligible incidence of septic complications in the choledochojejunostomy patients does not appear to warrant the administration of prophylactic antibiotics, as has been previously suggested.

Objectives: The purpose of this study was to review our experience with Epstein-Barr virus (EBV) hepatitis after liver transplantation., Methods: During a 68-month period, we performed 668 liver transplants and 585 patients. We identified 11 patients (2 percent), including 5 adults and 6 children with EBV hepatitis after liver transplantation. The diagnosis of EBV hepatitis was established by evaluating allograft biopsies. The histology was confirmed by the use of polymerase chain reaction technology., Results: The average time of diagnosis after liver transplantation was 45 days. Eight of eleven cases occurred within the first six months after transplantation. After the diagnosis of EBV hepatitis, treatment consisted of a decrease in immunosuppression plus antiviral therapy and intravenous immunoglobulin. The one-year actuarial survival for patients with EBV hepatitis, was 73 percent (8 of 11). Two patients died of progressive multi-organ EBV involvement. To determine the risk of developing EBV hepatitis, we reviewed our experience with the administration of antilymphocyte preparations in 585 patients. The patients found to have a significantly greater risk of developing EBV hepatitis included those receiving more than one course of antilymphocyte therapy or greater than a total dose of 70 milligrams of OKT3 in a single course., Conclusions: EBV hepatitis after liver transplantation is an infrequent event, which may be treated successfully. The occurrence of EBV hepatitis appears closely linked to the use of antilymphocyte preparations.

Bile acid metabolism and biliary secretion were characterized in the first 2 wk after orthotopic liver transplantation in 15 patients receiving cyclosporine and in five patients receiving FK 506. Analyses were performed on hepatic bile obtained by T-tube drainage; values obtained were compared with literature values for bile samples obtained in patients who had undergone cholecystectomy. Biliary bile acid output, which is equivalent to bile acid biosynthesis from cholesterol, was low (mean +/- S.E.M.) and increased with time: day 1, 0.50 +/- 0.1 mmol/day; day 3, 0.8 +/- 0.1 mmol/day; and day 6, 1.6 +/- 0.5 mmol/day. Chenodeoxycholic acid biosynthesis, as percent of total bile acid biosynthesis, was abnormally low in patients receiving cyclosporine (16.2 +/- 1.1) but not in patients receiving FK 506 (38.2 +/- 4.8) (p < 0.005). Before the T-tube was clamped, the proportion of deoxycholic acid (a secondary bile acid formed by bacterial 7-dehydroxylation of cholic acid) was low in both groups: cyclosporine, 0.4 +/- 0.1; FK 506, 4.8 +/- 2.5 (p < 0.01). The mean concentration of bile acids in hepatic bile between days 4 and 11 did not differ significantly between groups: cyclosporine, 7.7 +/- 1.3 mmol/L; FK 506 4.3 +/- 0.7 mmol/L (mean +/- S.E.M.). (These values are similar to those reported for patients who have undergone cholecystectomy.) Bile acid-dependent bile flow, expressed as apparent choleretic activity (microliters of bile per micromole of bile acid output), was markedly elevated: in patients receiving cyclosporine the value was 129, and in patients receiving FK 506 the value was 220. (In patients who have undergone cholecystectomy, this value is less than 30).(ABSTRACT TRUNCATED AT 250 WORDS)

Six transplantations of the liver were performed over a period of six years in five adult patients with Type I diabetes mellitus (DM). The diabetic group included two males and three females with a mean age of 36 years and a mean duration of DM of 20 years. Primary diseases of the liver included two instances of primary biliary cirrhosis, two instances of sclerosing cholangitis and one instance of autoimmune chronic hepatitis. Three patients also received a simultaneous whole organ pancreatic transplant. All patients were managed with cyclosporine and prednisone immunosuppression with selective OKT3 induction. Patient and hepatic allograft survival rates were 80 and 67 percent, respectively, after a mean follow-up period of 4.7 years. One of the three pancreatic grafts was successful and resulted in euglycemia for two years. Three patients have subsequently undergone successful renal transplantation at one, two and one-half, and six and one-half years after hepatic transplantation. Although transplantation of the liver can be performed safely in carefully selected patients with Type I DM, these patients are still at risk for the development of progressive nephropathy. Renal transplantation is an acceptable therapeutic alternative when this occurs.

Acute hepatic failure developed after 8-methoxypsoralen and ultraviolet irradiation for psoriasis in a patient with prior methotrexate-induced cirrhosis. Review of the literature and the temporal relationship between 8-methoxypsoralen and hepatic injury in our patient suggests it may be a direct hepatotoxin. In our report, submassive necrosis superimposed on cirrhosis appears to have produced hepatic failure.

We have used extracorporeal liver perfusion (ECLP) to aid in the management of three patients with fulminant hepatic failure (FHF). Organs were used for ECLP only if they would have gone otherwise unused through United Network for Organ Sharing. In all three patients treated, serial serum bilirubin and arterial ammonia values trended toward the normal range. The neurologic examinations improved dramatically in two patients, and metabolic function of the extracorporeally perfused livers was unequivocally demonstrated by the clearance of theophylline in the last two patients. Two patients ultimately had successful liver transplants, whereas the third patient failed to improve neurologically despite evidence of metabolic function by the extracorporeally perfused liver, and died 7 days after ECLP was discontinued, from pulmonary and renal failure. These studies suggest that, 30 yr after initial clinical trials, ECLP can be applied safely without the need for arterial access 1) as a bridge to transplantation, 2) to assess whether patients in FHF will benefit from improved hepatic function and therefore transplantation, and 3) potentially, to evaluate the "usability" of questionable donor organs.

Background: The results of orthotopic liver transplantation (OLTx) in patients with diabetes mellitus (DM) are not well defined., Methods: Between 1985 and 1991, 45 adult patients with pretransplantation DM (5 type I, 40 type II) underwent OLTx at our center as identified by retrospective chart review. We compared this diabetic recipient group to a case-control nondiabetic group matched for age, gender, primary liver disease, weight, and timing of OLTx. A total of 30 variables were collected and analyzed with McNemar's test for categorical data, paired t tests for continuous data, and survival and repeated measures analysis for longitudinal data., Results: No differences between diabetic and nondiabetic recipients were noted in patient or graft survival, the incidence or severity of rejection, blood transfusions, operative complications, readmissions, major infections, or number of hospital days after OLTx. However, the incidence of minor bacterial (p = 0.046) and minor fungal (p = 0.035) infections were higher in the DM group. Serum blood urea nitrogen (p = 0.02) and creatinine (p = 0.03) levels were also higher in patients with diabetes versus control patients during the first year after OLTx., Conclusions: In carefully selected patients with pretransplantation DM, OLTx can be accomplished with results similar to nondiabetic recipients in spite of a higher incidence of minor infections and renal dysfunction.

Cyclosporine is used in the postoperative management of rejection in liver allograft recipients. Despite its efficacy in the treatment of allograft rejection, the drug exhibits toxicity at elevated whole blood concentrations including nephrotoxicity with associated histologic changes, and evidence of hepatotoxicity as determined by liver function studies. To date, there have been few published reports describing histologic changes in liver biopsies from patients with elevated blood cyclosporine levels. In the present study, we retrospectively examined biopsies from 16 liver allograft recipients, seven patients with elevated whole blood cyclosporine levels (> 1000 ng/ml) and nine control patients who had whole blood cyclosporine levels in the therapeutic range (558 to 993 ng/ml). In each case, frozen liver biopsy tissue was available to measure tissue levels of cyclosporine and metabolites. The blood and tissue drug levels were then correlated with the histologic changes present in the biopsy specimens. Patients with increased cyclosporine levels displayed histologic changes consisting of hypertrophy of the bile ductal epithelium with cytoplasmic vacuoles and the presence of "foamy" material within the hepatic sinusoids that were either absent or occurred less frequently in the control group. The histologic changes correlated best with cyclosporine metabolite levels rather than tissue levels of native drug. When liver function studies were correlated with cyclosporine levels, only gamma glutamyl transpeptidase (GGT) demonstrated a significant positive correlation with the histologic changes.(ABSTRACT TRUNCATED AT 250 WORDS)

We report coexistent collagenous colitis and collagenous sprue in a 62-year-old woman with diarrhea. Investigations suggested malabsorption, and small intestinal biopsies demonstrated a flattened mucosa with subepithelial collagen deposition. Colonic biopsies also showed a thickened subepithelial collagen band as well as a striking lamina propria inflammatory cell infiltrate. Symptomatic remission was induced with a gluten/lactose-free diet, oral prednisone, and sulfasalazine and has been maintained with gluten restriction alone. Repeat biopsies after 2 months demonstrated restoration of normal small intestinal and colonic collagen bands; only a chronic inflammatory cell infiltrate (consistent with microscopic/lymphocytic colitis) persisted in colonic biopsies. We propose that, in this instance, collagenous enterocolitis represented a diffuse manifestation of gluten sensitivity.

Cytomegalovirus is the single most important pathogen in clinical transplantation. Although much progress has been made in our understanding of the molecular biology and epidemiology of CMV infection and in our ability to diagnosis and treat CMV disease, it remains a major cause of morbidity but is no longer a major cause of mortality after liver transplantation. Risk factors for CMV disease after liver transplantation include donor and recipient serologic status, the use of antilymphocyte therapy, and retransplantation. CMV disease occurs early after transplantation, and the most frequent site of disease is the hepatic allograft. We have treated 79 patients with intravenous ganciclovir, with ultimate control of disease achieved in 69 patients (87.3%). Preliminary results using intravenous immunoglobulin and oral acyclovir for CMV prophylaxis in high-risk patients have been encouraging. In addition to producing clinical syndromes. CMV may have direct immunologic effects and is a marker of the net state of immunosuppression.

We performed fasting and postprandial recordings of antroduodenal manometry in 21 normal volunteers, 13 patients with insulin-dependent diabetes mellitus and gastrointestinal symptoms, and 11 patients with the irritable bowel syndrome. None of the patients or volunteers had previously undergone an intestinal intubation study. Recordings could not be obtained from four of the diabetic patients due to failure to intubate the pylorus. Catheter migration led to incomplete antral data in a further 21% of all recordings. Due to the wide variations demonstrated by the normal volunteers, parameters of either the migrating motor complex (MMC) or the fed response could not differentiate between either of the patient groups and/or the controls. Similarly, while abnormal patterns of either fasting or postprandial motility were common in the diabetic patients, manometry had a sensitivity of only 67% in comparison to the less invasive radionuclide gastric emptying study. Furthermore, manometry failed to identify any diagnostic abnormality in irritable bowel patients; in particular, the incidence of "clustered" contractions was similar in all three groups. We conclude that short duration antroduodenal manometry is of limited diagnostic usefulness due to the difficulties in pyloric intubation in the presence of a dilated stomach and the intrinsic variability in normal motor patterns, perhaps excerbated by the stressful effects of the procedure itself in tube-naive subjects.

Based on our 7 and one-half-year experience with liver transplantation at the University of Nebraska Medical Center: 1. Success and growth of the program has been, in part, the result of close interaction and support of the various specialists involved. 2. We have demonstrated that outstanding patient and graft survival rates can be obtained with cyclosporine/prednisone immunosuppression. 3. Few, if any, technical contraindications exist to liver transplantation. 4. Surgical advances have allowed allografts to be salvaged which would otherwise require replacement. 5. Routine donor-liver biopsy prior to implantation has reduced the rate of primary nonfunction. 6. New strategies to improve survival for patients with hepatitis-B-related liver disease and hepatic malignancies undergoing liver transplantation need to be developed. 7. The management of patients with fulminant hepatic failure is evolving and now includes innovative approaches such as the use of ECLS and auxiliary transplants.

Unlabelled: During a 38-month period, we studied 320 liver transplants in 283 recipients (202 adults, 81 children). CMV disease was documented in 85 patients (30.0%) The major risk factor for CMV disease was primary CMV exposure (transplanting a seropositive allograft into a seronegative recipient). A total of 42 patients (14.8%) had primary CMV exposure. Twenty-one patients were historical controls, while the next 21 received prophylaxis for CMV infection in a nonrandomized trial of consecutive study groups. The regimen of prophylaxis consisted of intravenous immune globulin (IgG; 0.5 g/kg) at weekly intervals for 6 weeks and acyclovir for 3 months. CMV prophylaxis resulted in a dramatic reduction in the incidence of CMV disease (71.4% vs. 23.8%, (P less than 0.01). All cases of CMV were treated with intravenous ganciclovir (5 mg/kg b.i.d. for 14 days), with 5 patients in the control group developing recurrent CMV disease (33.3% relapse). In the 16 patients receiving prophylaxis who did not develop CMV disease, all developed positive CMV-IgG titers with the passive administration of IgG. However, none developed any evidence of CMV infection or viral shedding as assessed by IgM titers and surveillance viral cultures. Four deaths occurred (all control patients), but none were related to CMV disease. Overall patient and graft survivals after primary CMV exposure were 90.5% and 82.2%, respectively, after a mean follow-up of 14 months., Conclusion: Primary CMV exposure is a major risk factor for CMV disease in liver transplant recipients. Intravenous IgG plus acyclovir is safe and effective in preventing CMV infection and disease in this setting. Because of the scarcity of donor organs, we do not advocate protective matching to avoid primary CMV exposure but rather recommend prophylaxis to prevent CMV disease in this high-risk group.

Five patients with severe dysthyroid optic neuropathy were treated with intravenous methylprednisolone (1 g daily for 3 consecutive days). Before administration, visual acuity of the more severely affected eyes of each patient was counting fingers at 5 feet, 8/200, 20/400, 20/200, and 20/80. Immediately after completion of pulse therapy, visual acuity improved to 20/25 in four patients and 20/30 in one. Remissions were maintained with oral prednisone and external beam irradiation of the orbit. Pulse methylprednisolone therapy appears to be beneficial in the initial management of severe dysthyroid optic neuropathy.

Identifying the etiology of hepatic dysfunction in liver transplant patients is critical to their clinical management and in maintaining graft survival. While cytomegalovirus (CMV) is a well-known cause of posttransplant hepatitis, the morphologic diagnosis of CMV hepatitis in liver biopsies can be difficult. Because conventional tissue culture for CMV requires days to weeks, the final results often arrive too late to be clinically useful. In this study, 44 liver allograft biopsies from 21 patients with hepatic dysfunction were evaluated for CMV by routine light microscopy, conventional tissue culture, and in situ DNA hybridization (IH) using commercially available biotinylated CMV-specific DNA probes. Whereas 38.6% of the biopsy specimens were positive by IH, 15.9% were culture-positive biopsies and 13.6% were positive by routine light microscopy. Assuming tissue culture to be the standard, IH demonstrated a sensitivity of 100% and a specificity of 73%. In comparison, routine light microscopy showed a sensitivity of 71.4% and specificity of 97.3%. In addition, three biopsy specimens positive only by IH were from three patients who had other liver biopsies positive for CMV by either light microscopy or viral culture. In situ DNA hybridization allows rapid detection (5-6 h) of CMV in paraffin-embedded liver allograft biopsies; it also has a sensitivity that surpasses routine histologic examination and perhaps even tissue culture.

Orthotopic liver transplantation can provide a large number of patients with end-stage liver disease an opportunity for significant improvement in long-term survival and quality of life. Transplantation should not be considered a last-ditch attempt to save a dying patient. Early referral of patients to transplant centers will allow for further improvement in survival of patients after transplantation. Ongoing communication between the referring physician and the transplant team is important in keeping abreast of changes in the patient's status so that optimal timing of the transplant may be achieved.

Biliary tract complications are a continuing source of morbidity after liver transplantation. In a 3.5-year period we performed 264 liver transplants in 226 patients (132 adults, 94 children). Biliary tract reconstruction was via Roux limb choledochojejunostomy (n = 144) or choledochocholedochostomy (n = 118). Fifty (19.1%) biliary complications occurred, and 35 (13.4%) necessitated operative repair. The incidence was similar in adults and children and after each method of reconstruction. Risk factors were vascular thrombosis and reduced-sized transplants. Diagnosis was based on the algorithmic use of multiple modalities with early biliary visualization. Roux limb complications usually occurred in the first month after transplant and necessitated operative intervention, whereas duct-to-duct problems appeared later and were more accessible to percutaneous or endoscopic manipulations. Eight (6.8%) patients required conversion to a Roux limb, whereas 8/15 (53.3%) cases of biliary stricture were successfully managed nonoperatively. Three (1.3%) patients and four (1.5%) grafts were lost as a result of biliary complications. One-year actuarial patient survival is 76.4% with a mean follow-up of 13.2 months. Early recognition of biliary complications and prompt interventional therapy can effectively prevent long-term sequelae. Although choledochocholedochostomy is more physiologic and expeditious, Roux-en-Y choledochojejunostomy remains a safe and versatile alternative and is the preferred method of reconstruction in select cases.

The proliferation of liver transplant services across the country during the next 5 years will be an interesting phenomenon to observe. An enlightened approach to the process require answers to several essential questions, many of which are discussed elsewhere in this issue of Seminars. Regardless of how the future distribution of services sorts out, many physicians will face an increasing likelihood that their services will be requested in the long-term management of liver transplant recipients. In this report, the care of liver transplant patients is discussed, including that involving the immediate post-operative phase, the in-hospital recovery, and the early and long-term care of outpatients. The discussion is limited to the more common problems that these patients experience. Information from available literature is interspersed with our experience to provide a personal approach to the diagnosis and treatment of both complications and normal post-transplant clinical concerns. Part of what the reader should obtain from a general review of a complex subject is an awareness of the amount of information that the review does not contain. We have touched the surface of a large number of topics, but have come up far short of a comprehensive coverage of all aspects of the postoperative care of the liver recipient. It is hoped that we have provided enough information to serve the reader as an initial foundation for building a more complete understanding of the management of liver transplant patients.

During a 43-month period, we performed 248 liver transplantations in 211 patients (127 adults and 84 children). Cytomegalovirus (CMV) disease was documented in 73 recipients (34.6%). Risk factors for CMV disease included donor CMV seropositivity, antilymphocyte therapy, and retransplantation. The mean time of occurrence of CMV disease was 38.3 days after transplantation, and the most frequent site of disease was the hepatic allograft. A total of 69 patients were treated with intravenous ganciclovir, with a prompt and lasting response documented in 51 (73.9%). The remaining 18 (26.1%) developed recurrent CMV disease, which was more common after primary CMV exposure. Cytomegalovirus disease was ultimately controlled by ganciclovir in 94.2% of cases. This disease occurs early after transplantation and can be related to well-defined risk factors. Although ganciclovir therapy is effective, preliminary experience with prophylaxis shows promise in reducing the incidence of CMV disease.