Krishnaswami Vijayaraghavan, MD, MS, FACC, FACO, FCCP

• Professor of Medicine, Midwestern University
• Glendale, Arizona
• Medical Director
• CV Research, Scottsdale Healthcare
• Scottsdale, Arizona

Effect of high-normal compared with low-normal arterial pH on protein balances in automated peritoneal dialysis patients arthritis relief for cats buy plaquenil in india. Adverse effects of systemic glucose absorption with peritoneal dialysis: How good is the evidence Icodextrin improves fluid and metabolic management in high and high-average transport patients arthritis knee grade 3 quality 200mg plaquenil. Management of hyperlipidemia in patients on peritoneal dialysis: current approaches rheumatoid arthritis journal plaquenil 400mg mastercard. Oral sodium bicarbonate for the treatment of metabolic acidosis in peritoneal dialysis patients: a randomized placebo-control trial arthritis ribs order 400 mg plaquenil amex. New onset hyperglycemia in nondiabetic chinese patients started on peritoneal dialysis gouty arthritis in fingers treatment order plaquenil 400mg mastercard. Serum potassium and cause-specific mortality in a large peritoneal dialysis cohort arthritis disability 400 mg plaquenil fast delivery. Dialysis modality and correction of metabolic acidosis: relationship with all-cause and cause-specific mortality. These include effects of illness and treatment, functional limitations and sexual dysfunction, dietary restrictions, time constraints, and fear of death. In addition, there may be marital conflict, strained interpersonal relationships with family and administrative or medical personnel, and socioeconomic concerns regarding costs of treatment and unemployment. Hospitalization rates for psychiatric disorders are high relative to other chronically ill patients. Common problems include depression, dementia and delirium, psychosis, personality and anxiety disorders, and substance abuse. Depression is the most common, as well as the most important, problem because of the risk of resulting noncompliance with the dialysis and/or medication regimen and the risk of suicide. The last criterion, (g), is probably the most specific, as some of the others are associated with uremia per se. Screening for underlying depression in the dialysis population is an important element of the treatment plan. In addition to the risk of suicide, depression may lead to poor compliance with the dialysis prescription, to abnormal immunologic function, or to anorexia and poor nutritional status. Some studies have suggested that baseline depressive symptomatology is associated with increased mortality, even after multiple medical risk factors have been accounted for in analyses. Important risk factors include a previous history of mental illness, recent hospitalization, age >75, male gender, white or Asian race, and alcohol or drug dependence. Treatment options for depression include pharmacotherapy, psychotherapy, including cognitive behavioral therapy, and electroconvulsive therapy. If efficacy is not achieved, then a switch to another antidepressant of the same class or a different class is a reasonable step. A dose of 20 mg of fluoxetine daily is usually well tolerated, although data are limited to the short term. Other medications in this same family include paroxetine, sertraline, and citalopram. Bupropion has active metabolites that are almost completely removed by the kidney. These metabolites may accumulate in dialysis patients, predisposing them to developing seizures. Denial is common and is a way of coping with uncomfortable thoughts or feelings related to being a "dialysis patient. However, these patients may resist treatment, as the implication is that "there is something wrong" with them. Supportive psychotherapy in conjunction with pharmacologic treatment is important for decreasing the rate of relapse. One uncontrolled study showed participation in group therapy sessions at the dialysis unit was associated with improved patient survival. Finally, electroconvulsive therapy may be used for patients with Chapter 30 / Psychosocial Issues 531 severe refractory depression, provided that there are no contraindications. Cognitive deficits may be related to underlying uremia or other coexistent underlying medical conditions, as described in more detail in Chapter 40. Physicians should initiate discussions with the family about cessation of dialysis in patients with progressive dementia. Withdrawal from dialysis is relatively common, especially in elderly patients or patients who fail to thrive. Advanced directives should be offered to patients at the initiation of renal replacement therapy, ideally before the onset of any disease that would impair their capacity for decision making. There was a 45% prevalence of anxiety disorders in a single center study of 70 hemodialysis patients. Disruptive behavior directed toward the dialysis staff occurs in a minority of patients, but nevertheless can be a disturbance to all those in the dialysis unit. It is important to try to understand why the patient is angry and to explore potential solutions. Setting limits or establishing boundaries is paramount when hostility or aggression poses a threat of harm to the patient or to others. Hostility and aggressive behaviors might be manifestations of an underlying psychiatric symptom, such as paranoia, referential thinking, or even conditions associated with delirium. If doubt about a particular patient exists, consultation with a psychiatrist should be sought. If these measures are not effective, short-acting benzodiazepines such as lorazepam or alprazolam may be prescribed for limited periods. The use of diazepam and chlordiazepoxide should be avoided in dialysis patients, owing to their metabolism to pharmacologically active metabolites. Barbiturates should not be used in place of benzodiazepines, since the long-acting ones are removed by hemodialysis. For the acutely agitated patient, antipsychotic medications, such as haloperidol, are sometimes required. Haloperidol is not renally cleared; therefore, no dose adjustment is usually necessary. Little is known about the effects of other atypical antipsychotics, such as risperidone or olanzapine, in this patient population. Lithium is cleared by dialysis; therefore, the dose should be given after each dialysis treatment. Valproic acid is another mood stabilizer sometimes used to treat bipolar disorder. Free serum levels of this drug have been observed to be elevated in patients with impaired renal function. Caution should be exercised in the administration of glucocorticoids to potential renal transplant patients with a history of psychosis, because of the risk of steroid-induced psychosis. Marital conflict may be associated with a patient,s perception of burden of illness and the degree to which a patient does not adhere to the dialysis prescription. Marital satisfaction and conflict may be particularly salient for female patients. Problems include decreased libido, erectile dysfunction, menstrual disorders, and infertility. Impotence is believed to occur in roughly 70% of men treated with dialysis, and men about to initiate dialysis should be counseled regarding the possibility of erectile dysfunction. This may lead to better communication with the physician and therefore reduce the possibility of depression. Women treated with dialysis commonly have disturbances in fertility and menstruation. Irregular menstrual cycles are common after the initiation of hemodialysis treatment. Those holding professional occupations may have greater flexibility in their work schedules and may be more likely to continue employment. Unemployment can have a significant psychologic impact on the individual, possibly contributing to a greater likelihood of depression. Exercise may play an important role in improving a patient,s overall sense of well-being. Specially designed exercise programs are available for those with physical impairments, and these should be promoted at the dialysis center or during routine physician visits. Other therapeutic modalities to consider are stress reduction/relaxation exercises and Chapter 30 / Psychosocial Issues 533 biofeedback, which have been successfully used, especially in managing disruptive and unstable patients. This is especially important when making decisions regarding the initiation or withdrawal of dialysis. There have been several recent clinical trials that evaluated the impact of intensification of dialysis prescriptions on patients, perceptions of quality of life. Atalay H, et al: Sertraline treatment is associated with an improvement in depression and health-related quality of life in chronic peritoneal dialysis patients. Psychosocial intervention improves depression, quality of life, and fluid adherence in hemodialysis. Depression and marital dissatisfaction in patients with end-stage renal disease and in their spouses. Relation between depression, some laboratory parameters, and quality-of-life in hemodialysis patients. A practical approach to the treatment of depression in patients with chronic kidney disease and end-stage renal disease. Palliative care in end-stage renal disease: focus on advance care planning, hospice referral, and bereavement [Review]. Multiple measurements of depression predict mortality in a longitudinal study of chronic hemodialysis patients. Depression in end-stage renal disease patients treated with hemodialysis: tools, correlates, outcomes, and needs. The frequency and significance of the "difficult" patient: the nephrology community,s perceptions. Chronic kidney disease and cognitive impairment in the elderly: the Health, Aging and Body Composition Study. Psychosocial variables, quality of life and religious beliefs in end-stage renal disease patients treated with hemodialysis. Shared decision making (guideline regarding withdrawal from dialysis and palliative care). Quality-of-life and psychosocial relationships in patients with chronic renal insufficiency. Treatment with antidepressive drugs improved quality-of-life in chronic hemodialysis patients. Screening for depression in chronic hemodialysis patients: comparison of the Beck Depression Inventory, primary nurse, and nephrology team. Changes in quality-of-life during hemodialysis and peritoneal dialysis treatment: generic and disease specific measures. Chronic peritoneal dialysis patients diagnosed with clinical depression: results of pharmacologic therapy. The identification and treatment of depression in patients maintained on dialysis. Patients with this syndrome have increased rates of hospitalization and mortality (Kalantar-Zadeh, 2004). In most instances, serum levels of inflammatory markers are increased, and numerous causes of chronic inflammation may be present (Kaysen, 2001). Proinflammatory cytokines can cause anorexia with suppression of nutrient intake (Kaizu, 2003). Chronic inflammation also is associated with cytokine-mediated hypermetabolism and resistance to anabolic actions of insulin leading to increased net protein catabolism (Siew, 2010). There is, however, an increasing incidence of obesity among patients initiating maintenance dialysis therapy (Kramer, 2006). Symptoms of nausea, vomiting, and anorexia, as well as recent changes in body weight, should be carefully evaluated to ascertain cause. Nonuremic causes of changes in weight and/or food intake must be kept in mind, including severe congestive heart failure, diabetes, various gastrointestinal diseases, and depression. Phosphate binders or oral iron preparations can cause dyspepsia and other gastrointestinal symptoms. Patient recall of food intake should be determined on both dialysis and nondialysis days, performed biannually (Kopple, 2001); intake on dialysis days typically is about 20% lower (Burrowes, 2003). Food frequency questionnaires may also provide useful information (Kalantar-Zadeh, 2002). Questions that are common to all screening tools include information about body weight changes within a given time frame, amount of oral intake, or lack of appetite. Comparison with prior values is important as both body weight and lean body mass decrease over time in hemodialysis patients (Di Filippo, 2006; Rocco, 2004). Skinfold thickness measured at the biceps or triceps provides an estimate of body fat, whereas midarm circumference can be used to estimate muscle mass. These measures can be compared with reference ranges established in wellnourished dialysis patients (Chumlea, 2003). Patients with values below the 25th percentile for either middle upper arm circumference or triceps skinfold thickness are likely to be malnourished. Bioimpedance analysis is based on the measurement of resistance and reactance when a constant alternating electrical current is applied to a patient.

The most common cause of increased dialysis solution conductivity is either a kink in the tubing routing purified water to the dialysis machine rheumatoid arthritis curable buy cheap plaquenil 200 mg on-line, or low water pressure arthritis pills names buy 200 mg plaquenil fast delivery, resulting in insufficient water delivery to the machine what does arthritis in your neck look like buy plaquenil 200 mg free shipping. The dialysis solution bypass valve is activated as soon as conductivity deviates from the specified limits arthritis pain commercial order plaquenil amex, diverting the abnormal dialysis solution away from the dialyzer to the drain arthritis in back ribs purchase plaquenil 200 mg without prescription. Abnormal temperature is usually caused by some malfunction in the heating circuit that warms the dialysate arthritis in cervical and lumbar spine purchase plaquenil 200mg with amex. Chapter 10 / Acute Hemodialysis Prescription 189 presence of air bubbles in the dialysis solution, to dialysate bilirubin in jaundiced patients, or to a dirty sensor. A blood leak alarm should be confirmed by testing the effluent dialysate with a test strip of the sort used for detecting hemoglobin in the urine. The manifestations and treatment of hypotension and other complications during dialysis are discussed in Chapter 12. The blood in the extracorporeal circuit can be returned using either saline or air. When air is used, the blood pump is first shut off, and the arterial blood line is clamped close to the patient. The arterial blood line is then disconnected just distal to the clamp, opening it to air. When the air reaches the venous air trap, or when air bubbles are first seen in the venous blood line, the venous line is clamped, the blood pump shut off, and the return procedure terminated. Use of air to return the blood increases the risk of air embolism, and the termination procedure should be extremely carefully supervised when air return is employed. False alarms may be due to the whenever possible, and the postdialysis weight compared with the predialysis weight. It is not uncommon for the weight loss to be greater or less than that anticipated on the basis of the calculated ultrafiltration rate. Blood can be sampled promptly after dialysis to confirm the adequacy of urea nitrogen removal and correction of acidosis. The method of obtaining the postdialysis blood sample is quite important; if access recirculation is present, contamination of the inlet blood sample with dialyzed outlet blood can occur, yielding erroneously low plasma urea nitrogen values. The timing of the sampling is critically important in that it can help discern access recirculation, cardiopulmonary recirculation, and intercompartmental rebound effects. Reliable methods of obtaining the postdialysis sample are described in Chapters 3 and 11. The methods described in Chapters 3 and 11 can be used to estimate a predicted Kt/V and urea reduction ratio. If the plasma urea nitrogen value has fallen to a lesser extent, possible causes include partial clotting of the dialyzer, an error in setting of the blood flow rate, and recirculation at the vascular access site. Online machine methods of monitoring in vivo dialyzer clearance (ionic conductance) and Kt/V (ultraviolet absorbance of the spent dialysate) are described in Chapter 11. The change in the plasma potassium level as a result of dialysis is difficult to predict because of concomitant shifting of potassium into cells due to correction of acidosis or to cellular uptake of glucose. In acute patients, it is best to sample blood for potassium at least 1 hour after the end of dialysis. Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion. Kayexalate (sodium polystyrene sulphonate) in sorbitol associated with intestinal necrosis in uremic patients. Central pontine and extrapontine myelinolysis after rapid correction of hyponatremia by hemodialysis in a uremic patient. Prescribing an equilibrated intermittent hemodialysis dose in intensive care unit acute renal failure. Effect of hemorrhagic reduction in blood pressure on recovery from acute renal failure. Cellulose, modified cellulose and synthetic membranes in the haemodialysis of patients with end-stage renal disease. Prevalence of detectable venous pressure drops expected with venous needle dislodgement. Dialysate magnesium concentration predicts the occurrence of intradialytic hypotension [Abstract]. Related articles, links influence of dialysis membranes on outcomes in acute renal failure: a meta-analysis. Effect of dialysate calcium concentrations in intradialytic blood pressure course in cardiac-compromised patients. A proposed approach to the dialysis prescription in severely hyponatremic patients with end-stage renal disease. Treatment of severe hyponatremia in patients with kidney failure: Role of continuous venovenous hemofiltration with low sodium replacement fluid. Although uremic toxicity is due to both small- and large-molecular-weight solutes, small toxins appear to be of greater importance. For this reason (and there are practical, laboratory measurement issues as well), the amount of dialysis prescribed is based on removal of urea, which has a molecular weight of 60 Da. Urea is only slightly toxic per se, and so its plasma level is only reflecting concentrations of other, presumably more harmful, uremic toxins. If removal is inadequate, then dialysis is inadequate, regardless of the serum level. On the other hand, a low serum urea level does not necessarily reflect adequate dialysis. Serum level depends not only on the rate of removal but also on the rate of urea generation. The generation rate is linked to the protein nitrogen appearance rate because most protein nitrogen is excreted as urea. A low serum urea level may be found in patients in whom removal is poor but in whom the generation rate is also low. In a secondary analysis of the randomized National Cooperative Dialysis Study, the rate of treatment failure increased dramatically in patients dialyzed three times per week when spKt/V was <0. The European Best Practice Guidelines 192 Chapter 11 / Chronic Hemodialysis Prescription 193 recommend a slightly higher minimum amount of dialysis, defined as a minimum eKt/V of 1. Patients assigned to the higher dose of dialysis did not live longer, were not hospitalized less frequently, and were not found to manifest nutritional or other benefits. Apart from these two studies, there is little high-quality evidence regarding dialysis dose and outcomes, and almost all recommendations and guidelines in this area are primarily opinion-based. If one wishes to increase the dose of dialysis in terms of stdKt/V, the increase in spKt/V has to be increased by about twice as much. One can come up with four reasons why smaller patients should get relatively more dialysis when dose is measured as spKt/V: a. It is fairly easy to deliver a high Kt/V to small patients (and also women) in a short session length. Such short session lengths may not be sufficient to allow for removal of middle molecules, nor for adequate removal of excess fluid, and this may result in a chronically overhydrated patient. The thinking is that the increased amount of dialysis will help return the patient to his or her healthier, premorbid condition. Whether patients with substantial residual kidney function can be managed with lower doses of dialysis is an unanswered question. In one large study, when patient urine volume was >100 mL per day, the amount of dialysis delivered had little impact on survival (Temorshuizen, 2004). Methods of adjusting dialysis dose for residual kidney function are entirely opinionbased. There is no high-level evidence that can guide us in terms of dose titration when dialysis is given other than three times per week. In the developing world, many patients are dialyzed only twice a week for economic reasons, and in the United States, this was not unusual in the recent past. Kinetic modeling using an stdKt/V approach suggests that twice-a-week dialysis is not appropriate in patients without some modest degree of residual kidney function. One observational study of twice-a-week dialysis done in the United States was unable to show an adverse association for this treatment strategy, and outcomes were actually a bit better than in patients dialyzed three times per week. Lack of harm may have been due to preferential selection of patients with some residual kidney function (Hanson, 1999), but there was no definitive evidence that this was the case. For solutes such as phosphorus and middle molecules, total weekly time is the major determinant of removal. Short weekly time also makes it difficult to remove excess salt and water from patients safely and effectively. The European Best Practices Group (2002) recommends a minimum 4-hour treatment time. Also, dose-versus-outcomes data may be confounded by dose-targeting bias, a situation where survival is higher in patients who are meeting whatever dose target is being applied (Daugirdas, 2013). A large randomized study (TiMe trial) is currently underway in the United States to determine whether setting a minimum dialysis time of 4. Another argument against Kt/V is that a focus on urea removal tends to drive high-efficiency dialysis, with use of large dialyzers and rapid blood flows; the high efficiency of such treatments may result in solute disequilibrium and intradialytic side effects. Also, high blood flow rates delivered using the requisite larger needle sizes may engender more blood turbulence and platelet activation, as well as access dysfunction. A related question is whether one should make "optimum" use of the dialysis time by prescribing the highest blood flow that is consistently achievable, and using the most efficient (high K 0 A) dialyzer that one can afford. An alternative "slow and gentle" approach remains popular in Europe, according to which low blood flow rates and relatively small dialyzers are used. There are no randomized trials available to help choose between these two options. The best approach may be to set targets on the basis of both Kt/V (perhaps with higher minimum targets for women and smaller patients) and dialysis time. Changing the Kt/V target to a surface-area-adjusted value by itself solves the problem of short dialysis time given to smaller patients and women, as the amount of dialysis given to such patients based on surface area needs to be considerably larger, and this takes more time to deliver. A dialysis prescription involves two main components: K, the dialyzer clearance, and t, the dialysis session length. This represents the total volume of blood cleared of urea during the dialysis session. This is best done from anthropometric equations incorporating height, weight, age, and gender as devised by Watson (Appendix A). A variety of urea modeling programs are available that will do a computer simulation of various scenarios and come up with many possible combinations of K and t. Internet-based calculators can be accessed via the Web References cited at the end of this chapter. At this point, you are on a K0A line of about 900, so a dialyzer with a K0A value of at least 900 mL/min will be needed. If such a high-efficiency dialyzer is not available, one will need to dialyze longer than 4 hours. However, with some modern dialyzers that include spacer yarns to optimize dialysate flow around the fibers, increasing dialysate flow from 600 to 800 mL/min was shown to have very little impact (Ward, 2011). Often, one has a choice between using a larger (more expensive) or a smaller (slightly cheaper) dialyzer. What would the dialysis session length then need to be to achieve a target spKt/V of 1. Of the two dialyzers available, we look up their K0A (maximum clearance) values and find they are 1,400 mL/min for the larger one and 800 mL/min for the smaller one. We find that the K values are about 270 mL/min for the bigger (K0A = 1,400) dialyzer and 220 mL/min for the smaller (K0A = 800) dialyzer. In the presence of access recirculation, the postdialysis blood may be low due to admixture with dialyzer outlet blood unless a slow-blood-flow or a stop-dialysate-flow technique is used. Depending on whether 0%, 3%, or 6% of the body weight was removed during the dialysis treatment, the delivered spKt/V for that treatment will be 1. These programs are available commercially, and one, Solute Solver, is available on the Internet.

More mature fibrous septa with well differentiated fibroblasts and collagen may also be seen arthritis back bone spurs discount plaquenil 400mg with amex. Islands of osteoid-like tissue composed of a smooth eosinophilic matrix containing lacunae filled with one or more cells are the hallmark of the mixed lesion cmc arthritis definition 400mg plaquenil overnight delivery. While 40-60% of patients are considered inoperable at the time they are first seen and 10-20% have pulmonary metastases rheumatoid arthritis tmj discount 400mg plaquenil with amex, preoperative chemotherapy and transplantation for the more extensive lesions have resulted in resectability for nearly 90% of cases arthritis pain relief otc cheap plaquenil online visa. Precursor lesions and benign tumours Precursor lesions of hepatoblastoma have not been identified cure to arthritis in the knee buy discount plaquenil 400mg line, but hepatoblastoma must be differentiated from other liver tumours and pseudotumours that occur in the same age period rheumatoid arthritis diet recipes free cost of plaquenil. Infantile haemangioendothelioma, the most commonly occurring benign tumour of the liver, is seen almost exclusively in the first year of life and presents as an asymptomatic mass or, less frequently, as congestive heart failure due to rapid shunting of blood through the liver 1708. It is important to differentiate these teratoid features from a true teratoma, which does not contain fetal and embryonal epithelial hepatoblastoma areas. There is, however, a single case report of a discrete cystic teratoma contiguous to a hepatoblastoma 331. The one to two-cell thick trabeculae of fetal epithelial hepatoblastoma pattern are seen on the right. Areas showing mesenchymal tissue and foci of osteoid-like material are present, together with areas of epithelial hepatoblastoma. Focal nodular hyperplasia and nodular regenerative hyperplasia may be seen in the first few years of life but are more common in older children 1839. Hepatocellular adenoma is rarely seen in the first 5-10 years of life, but may be difficult to differentiate from a pure fetal epithelial hepatoblastoma. Genetic susceptibility Congenital anomalies are noted in approximately 5% of patients (Table 8. Other syndromes with an increased incidence of hepatoblastoma include Beckwith-Wiedemann syndrome, trisomy 18, trisomy 21, Acardia syndrome, Goldenhar syndrome, Prader Willi syndrome, and type 1a glycogen storage disease 1585. Increased copy numbers of c-met and K-sam proto-oncogenes and cyclin D1 genes have been described in a case of hepatoblastoma in an adult patient 977. The presence of oval cell antigen has been demonstrated in hepatoblastomas, which supports the stem cell origin of these tumours 1631. Prognosis and predictive factors Prognosis is directly affected by the ability to resect the lesion entirely, i. Chemotherapy and transplantation have allowed resectability in 90% of cases, increasing the overall survival to 65-70%. Other factors positively influencing prognosis include tumour confined to one lobe, fetal epithelial growth pattern, and multifocal dissemination (rather than unifocal growth pattern in the liver with distant metastases and vascular invasion) 2022. Wotherspoon Definition Primary lymphoma of the liver is defined as an extranodal lymphoma arising in the liver with the bulk of the disease localized to this site. Contiguous lymph node involvement and distant spread may be seen but the primary clinical presentation is in the liver, with therapy directed to this site. It is mainly a disease of white middle aged males 1043, 1217 although an occasional case has been reported in childhood 1557. Patients are almost always male (M:F approximately 5:1) but are usually younger with a mean age of 20 years (range 8-68 years) 334. In contrast to primary lymphoma, secondary liver infiltration is a frequent occurrence, being present in 80-100% of cases of chronic leukaemia, 50-60% of cases of non-Hodgkin lymphoma and approximately 30% of cases of multiple myeloma 2042, 261. Aetiology A proportion of cases are associated with hepatitis C virus infection with and without mixed cryoglobulinaemia 390, 56, 1257, 90, 371, 1625, 311. Clinical features the most frequent presenting symptoms are right upper abdominal/epigastric pain or discomfort, weight loss and fever 1043, 1217. Most cases are solitary or multiple masses within the liver which may be misdiagnosed as a primary liver tumour or metastatic cancer 1043, 1217. Some cases have been reported with diffuse infiltration of the liver associated with hepatomegaly but without a discrete mass, simulating hepatic inflammation 668. Hepatosplenic T-cell lymphomas present with hepatosplenomegaly, usually without peripheral lymphadenopathy and without lymphocytosis. Liver function tests are usually abnormal with moderate elevation of levels of transaminases and alkaline phosphatase. Histopathology B-cell lymphoma the majority of primary hepatic lymphomas are of diffuse large B-cell type with sheets of large cells with large nuclei and prominent nucleoli. Occasional cases of Burkitt lymphoma have been described 759 in which the morphology is typical of Burkitt lymphoma encountered elsewhere in the digestive tract. The atypical lymphoid cells have centrocyte-like cell morphology and surround reactive germinal centres. Lymphoepithelial lesions are formed by the centrocyte-like cells and the bile duct epithelium, and these may be highlighted by staining with anti-cytokeratin antibodies. Secondary involvement of the liver by chronic lymphocytic leukaemia and B-cell non-Hodgkin lymphoma tends to show a distribution involving the portal triads although nodular infiltration may also be seen with non-Hodgkin lymphoma and multiple myeloma 2042. Hepatosplenic T-cell lymphoma this is characterized by infiltration of the sinusoids by a monomorphic population of medium sized cells with a moderate amount of eosinophilic cytoplasm. The nuclei are round or slightly indented with moderately dispersed chromatin and contain small, usually basophilic, nucleoli. There may be mild sinusoidal dilation and there are occasional pseudo-peliotic lesions. A similar sinusoidal pattern of infiltration is seen in the spleen and bone marrow both of which are usually involved by the lymphoma at diagnosis 486, 334. All cases are negative for F1 and positive with antibodies for the T-cell receptor. Genetics Hepatosplenic T-cell lymphoma exhibits rearrangement of the T-cell receptor gene. Cytogenetic studies have shown isochromosome 7q in a number of cases and in some this has been present as the sole cytogenetic abnormality 524, 48 Prognosis the prognosis of primary hepatic lymphoma is generally poor. Chemotherapy or radiotherapy alone has been reported to be ineffective but combination modalities, including surgery in resectable cases, can give relatively good results. Nakanuma Definition Benign and malignant tumours arising in the liver, with vascular, fibrous, adipose and other mesenchymal tissue differentiation. Imaging Imaging studies establish the presence of a space-occupying lesion or lesions in the liver, and may provide a diagnosis or differential diagnosis 1565. It accounts for 8% of all liver tumours and pseudotumours from birth to 21 years of age, but during the first two years of life it represents 12% of all hepatic tumours and pseudotumours, and for 22% of the benign neoplasms 1839. It usually manifests in the first two years of life and there is a slight male predominance. Lesions involve the right lobe in 75% of cases, the left lobe in 22% and both lobes in 3%. Presentation is typically with abdominal swelling, but rapid accumulation of fluid in the tumour can cause sudden enlargement of the abdomen 1841. Macroscopically, it is usually a single mass that can attain a large size (up to 30 cm or more). The fate of untreated lesions is not known but there is no convincing evidence of malignant transformation. This tumour-like lesion is composed of loose connective tissue and epithelial ductal elements in varying proportions. Grossly, the cut surfaces exhibit solid, pink-tan areas and cysts containing a clear fluid. C Bile ducts display a ductal plate malformation; the primitive mesenchymal tissue consists of loosely arranged stellate cells. D Fluid accumulation in the mesenchyme mimics lymphangioma, but the spaces lack an endothelial lining. C the tumour is well circumscribed but not encapsulated, and consists of small vessels. D Masson trichrome stain shows vessels lined by a single layer of plump endothelial cells surrounded by a scant fibrous stroma. Fluid accumulation leads to separation of the fibres with formation of lymphangioma-like areas and larger cavities. The epithelial component consists of bile ducts that may be tortuous and occasionally dilated. Numerous arteries and veins are scattered throughout, as are foci of extramedullary haematopoiesis. Infantile haemangioendothelioma this lesion is defined as a benign tumour composed of vessels lined by plump endothelial cells, intermingled with bile ducts, that are set in a fibrous stroma. Infantile haemangioendothelioma accounts for about one fifth of all liver tumours and pseudotumours from birth to 21 years of age. It usually presents in the first two years of life, when it represents 40% of all tumours and pseudotumours and 70% of the benign ones 1839. There may be a variety of associated congenital anomalies, including hemihypertrophy and Cornelia de Lange syndrome. Patients may develop congestive heart failure or consumption coagulopathy, with or without an abdominal mass 397, 1708, and about 10% have haemangiomas of the skin. Grossly, infantile haemangioendothelioma forms a single large mass (55%) or involves the entire liver by multiple lesions (45%). The single tumours have a maximum diameter up to 14 cm while the multiple lesions are often less than a centimeter. The large, single lesions are redbrown or red-tan, often with haemorrhagic or fibrotic centers and focal calcification. Lesions are composed of numerous small vascular channels lined by plump endothelial cells usually arranged in a single layer, but multilayering and tufting can occur. The vessels are supported by a scanty fibrous stroma that may be loose or compact. Larger cavernous vessels with a single layer of flat endothelial cells are often present in the centre of the larger lesions; these vessels may undergo thrombosis with infarction, secondary fibrosis and calcification. Other characteristic features of infantile haemangioendothelioma are small bile ducts scattered between the vessels, and foci of extramedullary haematopoiesis. Infantile haemangioendothelioma has an overall survival of 70%; adverse risk factors include congestive heart failure, jaundice and the presence of multiple tumours 1708. Single tumours are generally resected although some 5-10% undergo spontaneous regression. Hepatic artery ligation or transarterial embolization are other therapeutic modalities. There are occasional reports of transformation of infantile haemangioendothelioma to angiosarcoma 1708. Cavernous haemangioma this is the most frequently occurring benign tumour of the liver. It is more frequent in females, and occurs at all ages but is least common in the paediatric age group. Although it usually presents in adults, it is thought to be a hamartomatous lesion. It is known to increase in size or even rupture during pregnancy, and also may enlarge or recur in patients on oestrogen therapy. When sectioned they partially collapse due to the escape of blood and have a spongy appearance. Lesions are typically composed of blood-filled vascular channels of varied size lined by a single layer of flat endothelial cells supported by fibrous tissue. Thrombi in various stages of organization with areas of infarction may be present, and older lesions show dense fibrosis and calcification. In sclerosed haemangiomas, most or all of the vessels are occluded and sometimes are only demonstrable by stains for elastic tissue. Angiomyolipoma the lesion is defined as a benign tumour composed of variable admixtures of adipose tissue, smooth muscle (spindled or epithelioid), and thick-walled blood vessels. The age range of angiomyolipoma is from 30-72 years, with a mean of 50 years 1373. Angiomyolipomas are usually single, with 60% located in the right lobe, 30% in the left lobe, 20% in both lobes and 8% in the caudate lobe 1373. They are sharply demarcated but not encapsulated, fleshy or firm and, when sectioned, with a homogeneous yellow, yellow-tan or tan appearance, depending on their content of fat. Angiomyolipomas are composed of adipose tissue, smooth muscle and thick-walled, sometimes hyalinized blood vessels in varying proportions. Morphologically and phenotypically they are believed to belong to a family of lesions characterized by proliferation of perivascular epithelioid cells 2197. The microscopic appearances are extensively varied and may imitate several malignant tumours. A characteristic feature of angiomyolipoma is the presence of extramedullary haematopoiesis. Mesenchymal tumours 193 Solitary fibrous tumour Solitary fibrous tumour has an age range from 32-83 years (mean, 57 years) 1270. Solitary fibrous tumour often shows alternating cellular and relatively acellular areas. The cellular areas consist of bundles of spindle cells arranged haphazardly or in a storiform pattern. In some cases the cells are arranged around ectatic vessels in a haemangiopericytoma-like pattern. Nuclei of the spindle cells are uniform and lack pleomorphism, but these tumours may undergo malignant change as evidenced by the presence of foci of necrosis, prominent cellular atypia, and mitotic activity in the range of 2-4 mitoses/10 hpf 1270, 514. The relatively acellular areas of solitary fibrous tumour contain abundant collagen bundles with thin, stretched-out tumour cells. Inflammatory pseudotumour this lesion is defined as a benign, nonneoplastic, non-metastasizing mass composed of fibrous tissue and proliferated myofibroblasts, with a marked inflammatory infiltration, predominantly plasma cells 318.

Syndromes

• Back pain
• Tobacco smoke or other irritants
• Asparagine, a protein found in the plant
• Choriocarcinoma (a type of cancer)
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Cytologically arthritis in dogs paracetamol discount plaquenil online mastercard, the cells exhibit irregular and hyperchromatic nuclei rheumatoid arthritis gwas order 200mg plaquenil amex, an increase in nuclear/cytoplasmic ratio and increased mitotic activity how does arthritis in neck feel purchase plaquenil with paypal. In low-grade dysplasia rheumatoid arthritis back pain effective 400mg plaquenil, the abnormalities are often confined to the lower half of the epithelium arthritis treatment mumbai buy 400 mg plaquenil mastercard, whereas in high-grade dysplasia the abnormal cells also occur in arthritis in dogs natural treatment cheap 400mg plaquenil fast delivery. Squamous cell carcinoma 15 A B middle third of the oesophagus, but multiple lesions occur. Histologically, cores of fibrovascular tissue are covered by mature stratified squamous epithelium. In Japan, oesophageal squamous cell carcinoma is diagnosed mainly based on nuclear criteria, even in cases judged to be non-invasive intraepithelial neoplasia (dysplasia) in the West. This difference in diagnostic practice may contribute to the relatively high rate of incidence and good prognosis of superficial squamous cell carcinoma reported in Japan 1682. Well differentiated tumours have cytological and histological features similar to those of the normal oesophageal squamous epithelium. The occurrence of keratinization has been interpreted as a sign of differentiation, although the normal oesophageal squamous epithelium does not keratinize. Poorly differentiated tumours predominantly consist of basal-type cells, which usually exhibit a high mitotic rate. Undifferentiated carcinomas are defined by a lack of definite light microscopic features of differentiation. However, ultrastructural or immunohistochemical investigations may disclose features of squamous differentiation in a subset of lightmicroscopically undifferentiated carcinomas 1881. Architectural disarray, loss of polarity and cellular atypia are much greater than shown in. Basal cell hyperplasia this lesion is histologically defined as an otherwise normal squamous epithelium with a basal zone thickness greater than 15% of total epithelial thickness, without elongation of lamina propria papillae 377. In most cases, basal cell hyperplasia is an epithelial proliferative lesion in response to oesophagitis, which is frequently observed in high-risk populations for oesophageal cancer 1547. It is a benign tumour composed of hyperplastic squamous epithelium covering finger-like processes with cores derived from the lamina propria. The polypoid lesions are smooth, sharply demarcated, and usually 5 mm or less in maximum diameter 249, 1428. Most squamous cell papillomas represent single isolated lesions, typically located in the distal to . C Well differentiated areas (left) contrast with immature basal-type cells of a poorly differentiated carcinoma (right). This autosomal, dominantly inherited disorder of the palmar and plantar surfaces of the skin segregates together with oesophageal cancer in three pedigrees, two of which are extensive 456, 1834, 693. The genetic defect is thought to be in a molecule involved in the physical structure of stratified squamous epithelia whereby loss of function of the gene may alter oesophageal integrity thereby making it more susceptible to environmental mutagens. How these various genetic events correlate with phenotypic Location of the tylosis oesophageal cancer gene by haplotype analysis 1cM/ 500 Kb. In the past, studies on prognostic factors were largely focused on patients who were treated by surgery, whereas factors influencing survival of patients treated by radiotherapy or by multimodal therapy have been investigated only rarely. All studies indicate that the depth of invasion and the presence of nodal or distant metastases are independent predictors of survival 1104, 895, 772. In particular, lymph node involvement, regardless of the extent of the primary tumour, indicates a poor prognosis 1862, 912, 1873. More recently, the prognostic significance of more sophisticated methods for the determination of tumour spread have been evaluated, including the ratio of involved to resected lymph nodes 1603, immunohistochemically determined lymph node micrometastases 824, 1327 and micrometastases in the bone marrow 1933. However, current data are still too limited to draw final conclusions on the prognostic value. The prognostic impact of tumour differentiation is equivocal, possibly due to the poor standardisation of the grading system and to the high prognostic power of tumour stage. Although some studies have shown a significant influence of tumour grade on survival 709, 772, the majority of studies have not 443, 1858, 1601, 1660. Other histopathological features associated with a poor prognosis include the presence of vascular and/or lymphatic invasion 772, 1662 and an infiltrative growth pattern of the primary tumour 1660. Intense lympho- cytic response to the tumour has been associated with a better prognosis 1660, 443. However, the proliferation index does not appear to be an independent prognostic factor 2189, 1005, 1659, 779. Regarding the prognostic impact, patients with diploid tumours usually survive longer than those with aneuploid tumours. The frequency of locoregional recurrence is negatively correlated with the distance of the primary tumour to the proximal resection margin and possibly to preoperative chemotherapy 1890, 1027. Other potential prognostic factors include growth factors and their receptors 927, oncogenes, including c-erbB-2 and int-2 778, cell cycle regulators 1748, 1297, tumour suppressor genes 1886, redox defence system components. Stein Definition A malignant epithelial tumour of the oesophagus with glandular differentiation arising predominantly from Barrett mucosa in the lower third of the oesophagus. Infrequently, adenocarcinoma originates from heterotopic gastric mucosa in the upper oesophagus, or from mucosal and submucosal glands. Aetiology Barrett oesophagus the epidemiological features of adenocarcinoma of the distal oesophagus and oesophagogastric junction match those of patients with known intestinal metaplasia in the distal oesophagus, i. Barrett oesophagus 1605, 1827, which has been identified as the single most important precursor lesion and risk factor for adenocarcinoma of the distal oesophagus, irrespective of the length of the segment with intestinal metaplasia. Intestinal metaplasia of the oesophagus develops when the normal squamous oesophageal epithelium is replaced by columnar epithelium during the process of healing after repetitive injury to the oesophageal mucosa, typically associated with gastro-oesophageal reflux disease 1798, 1799. Intestinal metaplasia can be detected in more than 80% of patients with adenocarcinoma of the distal oesophagus. A series of prospective endoscopic surveillance studies in patients with known intestinal metaplasia of the distal oesophagus has shown an incidence of oesophageal adenocarcinoma in the order of 1/100 years of follow up 1799. This translates into a life-time risk for oesophageal adenocarcinoma of about 10% in these patients. The length of the oesophageal segment with intestinal metaplasia, and the presence of ulcerations and strictures have been implicated as further risk factors for the development of oesophageal adenocarcinoma by some authors, but this has not been confirmed by others 1799, 1797, 1827. The biological significance of so-called ultrashort Barrett oesophagus or intestinal metaplasia just beneath a normal Z line has yet to be fully clarified 1325. Whether adenocarcinoma of the gastric cardia or subcardial gastric cancer is also related to foci of intestinal metapla- Epidemiology In industrialized countries, the incidence and prevalence of adenocarcinoma of the oesophagus has risen dramatically 1827. This is paralleled by rising rates of adenocarcinoma of the gastric cardia and of subcardial gastric carcinoma. It has been estimated that the rate of increase of oesophageal and oesophagogastric junction adenocarcinoma in the U. In the mid 1990s the incidence of oesophageal adenocarcinoma has been estimated between 1 and 4 per 100,000 per year in the U. In Asia and Africa, adenocarcinoma of the oesophagus is an uncommon finding, but increasing rates are also reported from these areas. In addition to the rise in incidence, adenocarcinoma of the oesophagus and of the oesophagogastric junction share some epidemiological characteristics that clearly distinguish them from squamous cell oesophageal carcinoma and adenocarcinoma of the distal stomach. These include a high preponderance for the male sex (male:female ratio 7:1), a sia at or immediately below the gastric cardia 715, 1797, 1722 is discussed in the chapter on adenocarcinoma of the oesophagogstric junction. Despite the broad advocation of endoscopic surveillance in patients with known Barrett oesophagus, more than 50% of patients with oesophageal adenocarcinoma still have locally advanced or metastatic disease at the time of presentation 1826. Chronic gastro-oesophageal reflux is the usual underlying cause of the repetitive mucosal injury and also provides an abnormal environment during the healing process that predisposes to intestinal metaplasia 1799. The more frequent, more severe, and longer-lasting the symptoms of reflux, the greater the risk. Among persons with long-standing and severe symptoms of reflux, the odds ratio for oesophageal adenocarcinoma was 43. Based on these data a strong and probably causal relation between gastro-oesophageal reflux, one of the most common benign disorders of the digestive tract, and oesophageal adenocarcinoma has been postulated. Factors predisposing for the development of Barrett oesophagus and subsequent adenocarcinoma in patients with gastrooesophageal reflux disease include a markedly increased oesophageal exposure time to refluxed gastric and duodenal contents due to a defective barrier function of the lower oesophageal sphincter and ineffective clearance function of the tubular oesophagus 1823, 1827. Experimental and clinical data indicate that combined oesophageal exposure to gastric acid and duodenal contents (bile acids and pancreatic enzymes) appears to be more detrimental than isolated exposure to gastric juice or duodenal contents alone 1241, 1825. Combined reflux is thought to increase cancer risk 20 Tumours of the oesophagus by promoting cellular proliferation, and by exposing the oesophageal epithelium to potentially genotoxic gastric and intestinal contents. Tobacco Smoking has been identified as another major risk factor for oesophageal adenocarcinoma and may account for as much as 40% of cases through an early stage carcinogenic effect 562, 2204. Obesity In a Swedish population-based case control study, obesity was also associated with an increased risk for oesophageal adenocarcinoma. The pathogenetic basis of the association with obesity remains to be elucidated 310. Alcohol In contrast to squamous cell oesophageal carcinoma, there is no strong relation between alcohol consumption and adenocarcinoma of the oesophagus. Helicobacter pylori this infection does not appear to be a predisposing factor for the development of intestinal metaplasia and adenocarcinoma in the distal oesophagus. Localization Adenocarcinoma may occur anywhere in a segment lined with columnar metaplastic mucosa (Barrett oesophagus) but develops mostly in its proximal verge. Adenocarcinoma in a short segment of Barrett oesophagus is easily mistaken for adenocarcinoma of the cardia. Since adenocarcinoma originating from the distal oesophagus may infiltrate the gastric cardia and carcinoma of the gastric cardia or subcardial region may grow into the distal oesophagus these entities are frequently difficult to discriminate (see chapter on tumours of the oesophagogastric junction). As an exception, adenocarcinoma occurs also in the middle or proximal third of the oesophagus, in the. The hypoechoic tumour lies between the first and second hyperechoic layers (markers). Barrett oesophagus Symptoms and signs Barrett oesophagus as the precursor of most adenocarcinomas is clinically silent in up to 90% of cases. The symptomatology of Barrett oesophagus, when present, is that of gastro-oesophageal reflux 1011. This is the condition where the early stages of neoplasia (intraepithelial and intramucosal neoplasia) should be sought. Histopathology Barrett epithelium is characterized by two different types of cells, i. Rarely, foci of complete intestinal metaplasia (type I) with absorptive cells and Paneth cells may be found. The mucous glands beneath the surface epithelium and pits may also contain metaplastic epithelium. Recent studies suggest that the columnar metaplasia originates from multipotential cells located in intrinsic oesophageal glands 1429. Intraepithelial neoplasia in Barrett oesophagus Macroscopy Intraepithelial neoplasia generally has no distinctive gross features, and is detected by systematic sampling of a flat Barrett mucosa 634, 1573. The area involved is variable, and the presence of multiple dysplastic foci is common 226, 1197. In some cases, intraepithelial neoplasia presents as one or several nodular masses resembling sessile adenomas. Rare dysplastic lesions have been considered true adenomas, with an expanding but localised growth resulting in a well demarcated interface with the surrounding tissue 1459. Endoscopy the endoscopic analysis of the squamocolumnar junction aims at the detection of columnar metaplasia in the distal oesophagus. At endoscopy, the squamocolumnar junction (Z-line) is in the thorax, just above the narrowed passage across the diaphragm. The anatomical landmarks in this area are treated in the chapter on tumours of the oesophagogastric junction. If the length of the columnar lining in this distal oesophageal segment is 3 cm, it is termed a long type of Barrett metaplasia. Single or multiple finger-like (1-3 cm) protrusions of columnar mucosa are classified as short type. In patients with short segment (< 3 cm) Barrett oesophagus the risk for developing adenocarcinoma is reported to be lower compared to those with long segment Barrett oesophagus 1720. As Barrett oesophagus is restricted to cases with histologically confirmed intestinal metaplasia, adequate tissue sampling is required. Microscopy Epithelial atypia in Barrett mucosa is usually assessed according to the system Table 1. T1 the 2nd hyperechoic layer (submucosa) is continuous the 2nd hyperechoic layer (submucosa) is interrupted the 3rd hyperechoic layer (adventitia) is continuous the 3rd hyperechoic layer (aventitia) is interrupted the hypoechoic tumour is continuous with adjacent structures T2 T3 T4 Adenocarcinoma 21 A B. A Haphazardly arranged glands (right) adjacent to hyperplastic squamous epithelium (left). B Goblet cells and columnar cells form villus-like structures over chronically inflamed stroma. If intraepithelial neoplasia is present, it should be classified as low-grade (synonymous with mild or moderate dysplasia) or highgrade (synonymous with severe dysplasia and carcinoma in situ) 1582, 1685. The criteria used to grade intraepithelial neoplasia comprise cytological and architectural features 75. Negative for intraepithelial neoplasia Usually, the lamina propria of Barrett mucosa contains a mild accompanying inflammatory infiltrate of mononuclear cells. There may be mild reactive changes with enlarged, hyperchromatic nuclei, prominence of nucleoli, and occasional mild stratification in the lower portion of the glands. However, towards the surface there is maturation of the epithelium with few or no abnormalities. These changes meet the criteria of atypia negative for intraepithelial neoplasia, and can usually be separated from low-grade intraepithelial neoplasia. One of the major challenges for the pathologist in Barrett oesophagus is the differentiation of intraepithelial neoplasia from reactive or regenerative epithelial changes. Note the numerous goblet cells showing a clear cytoplasmic mucous vacuole indenting the adjacent nucleus. In areas adjacent to erosions and ulcerations, the metaplastic epithelium may display villiform hyperplasia of the surface foveolae with cytological atypia and architectural disturbances. These abnormalities are usually milder than those observed in intraepithelial neoplasia. There is a normal expansion of the basal replication zone in regenerative epithelium versus intraepithelial neoplasia, where the proliferation shifts to more superficial portions of the gland 738.

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