Christopher B. Anderson, MD, MPH

• Assistant Professor, Urology
• Columbia University
• Medical CenterNew York, New York

https://www.cancer.columbia.edu/profile/christopher-b-anderson-md

Diagnosis cholesterol chart levels uk quality 20 mg atorlip-20, controversies cholesterol levels during menopause buy discount atorlip-20, and management of the syndrome of hemolysis cholesterol levels of athletes cheap atorlip-20 20mg with mastercard, elevated liver enzymes cholesterol levels in food chart purchase atorlip-20 american express, and low platelet count cholesterol over 200 discount atorlip-20 20 mg without a prescription. The two stage model of 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 preeclampsia: variations on the theme cholesterol medication nz generic atorlip-20 20 mg on-line. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Outcomes of severe pregnancyrelated liver disease: refining the role of transplantation. Continuing pathology following a hypertensive pregnancy and the risk of future disease. A fetal fattyacid oxidation disorder as a cause of liver disease in pregnant women. Effectiveness of combining plasma exchange with plasma perfusion in acute fatty liver of pregnancy: a retrospective analysis. Sexual functioning in patients with endstage liver disease before and after transplantation. Assessment of maternal and fetal risks in eleven patients and review of the management. Transjugular intrahepatic portosystemic shunt creation for recurrent gastrointestinal bleeding during pregnancy. Transjugular intrahepatic portosystemic shunt: a case report of rescue management of unrestrainable variceal bleeding in a pregnant woman. Prevalence of chronic hepatitis B virus infection in pregnant black women living in Soweto. Clinical and virological predictors of hepatic flares in pregnant Pregnancy and the Liver 585 women with chronic hepatitis B. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, doubleblind, placebocontrolled study. A prospective and openlabel study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. Telbivudine prevents vertical transmission of hepatitis B virus from women with high viral loads: a prospective longterm study. Efficacy and safety of telbivudine in different trimesters of pregnancy with high viremia for interrupting perinatal transmission of hepatitis B virus. Efficacy and safety of telbivudine treatment: an openlabel, prospective study in pregnant women for the prevention of perinatal transmission of hepatitis B virus infection. Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in reallife practice. Chronic hepatitis C virus infection is associated with increased risk of preterm birth: a metaanalysis of observational studies. Followup of pregnant women with autoimmune hepatitis: the disease behavior along with maternal and fetal outcomes. Outcomes of pregnancies in women with type 1 diabetes in Scotland: a national populationbased study. Longterm followup of babies exposed to azathioprine in utero and via breastfeeding. A population based cohort study of pregnancy outcomes among women with primary sclerosing cholangitis. Jaundice as the first manifestation of primary biliary cirrhosis during pregnancy: measurement of portal vein blood flow. Pregnancy outcome after liver transplantation: a singlecenter experience of 71 pregnancies in 45 recipients. Pregnancy after kidney and liver transplantation: its outcome and effect on the graft, mother, and neonate. Preconception counseling, fertility, and pregnancy complications after abdominal organ transplantation: a survey and cohort study of 532 recipients. Clinical course 94 109 95 110 96 111 97 112 98 113 99 114 115 100 101 116 102 117 103 104 118 119 120 105 106 121 107 and management of acute and chronic viral hepatitis during pregnancy. Pregnancyassociated acute liver disease and acute viral hepatitis: differentiation, course and outcome. Neonatal cholestasis resulting from vertical transmission of hepatitis A infection. Vertical transmission of hepatitis A resulting in an outbreak in a neonatal intensive care unit. Liver disease in pregnancy and its influence on maternal and fetal mortality: a prospective study from Chennai, Southern India. Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection. Experimental infection of pregnant rabbits with hepatitis E virus demonstrating high mortality and vertical transmission. Pregnant woman saved with liver transplantation from acute liver failure due to hepatitis E virus. Fatal disseminated herpes simplex virus infection in a previously healthy pregnant woman. Classification of hepatic venous outflow obstruction: ambiguous terminology of the BuddChiari syndrome. Report of 16 cases, with roentgenologic, hemodynamic and histologic studies of the hepatic outflow tract. The BuddChiari syndrome: correlation between hepatic scintigraphy and the clinical, radiological, and pathological findings in nineteen cases of hepatic venous outflow obstruction. Infants who develop severe or persistent jaundice should be investigated to exclude haemolysis, sepsis, or underlying liver disease. Neonatal jaundice, which persists beyond 14 or 21 days, should always be investigated even in breastfed babies. Biliary atresia is the single commonest cause of neonatal liver disease and the main indication for liver transplantation in children under the age of 5 years. Acute liver failure is a rare but fatal disease, with mortality of 70% without transplantation. Referral to a specialist unit, supportive management, and consideration for liver transplantation is essential. The commonest causes of chronic liver failure are extrahepatic biliary atresia or inherited metabolic liver disease in neonates, and autoimmune hepatitis and cystic fibrosis in older children. Nutritional support and management of hepatic complications have improved shortterm outcome. Liver transplantation for acute or chronic liver failure achieves good quality of life in over 80% of children long term. It is essential to recognize the effects of hepatic dysfunction on other body systems [1]. Biochemical tests Biochemical liver tests reflect the severity of hepatic dysfunction but rarely provide diagnostic information on individual diseases. Thus the most important inves tigation in neonates is fractionation of serum bilirubin into unconjugated and conjugated bilirubin, in order to differentiate between physiological or breastmilk jaun dice and liver disease. Aminotransferases are intracellular enzymes present in liver, heart, and skeletal muscle. These enzymes reflect nonspecific hepatic damage and may be normal in com pensated cirrhosis. In paediatric liver disease, increased levels above normal indicate biliary epithelial damage, malignant infiltration, cirrhosis, or osteopenia secondary to vitamin D deficiency. Extremely high levels of serum cholesterol may be found in prolonged cholestasis, particularly in Alagille syndrome. Low albumin indicates chronicity of liver disease, while abnormal coagulation indicates significant acute or chronic liver dysfunction. Bile acid metabolism Bile acid metabolism evolves during the final trimester of pregnancy and neonatal period. Immature conjugation and excretion during the first 3 months of life leads to reduced bile flow and pool size. A primitive pathway for fetal bile acid synthesis may be responsible for excretion of atypical cholestatic bile acids [3]. Radiology Abdominal ultrasonography provides information on liver and spleen size and echogenicity, gallbladder size, and presence of gallstones. It may identify tumours, hae mangiomas, abscesses or cysts within the liver, and allows targeted biopsy or aspiration. In fasted neo nates, a small or absent gallbladder suggests either severe intrahepatic cholestasis or biliary atresia. Radioisotope scanning is helpful in differentiating neo natal hepatitis (patchy uptake but good excretion) and biliary atresia (poor or absent excretion). Liver size Liver span in infants and children is measured by percus sion of the upper border and percussion/palpation of the lower border (Table 31. Circulatory factors and hepatic necrosis the portal vein largely supplies the right lobe of the fetal liver whereas the left receives highly oxygenated, placen tal blood, leading to heterogeneity in metabolic enzyme expression and haemopoesis [5]. At the time of birth, loss of placental blood can be followed by atrophy of the left lobe. This is related to poor placental blood supply and anoxia at the time of delivery. Localized liver necrosis may be due to herniation through anterior abdominal wall defects. Neonatal jaundice Almost twothirds of children who have liver disease present with prolonged neonatal jaundice. Although physiological jaundice is common, infants who develop severe or persistent jaundice should be investigated to exclude haemolysis, sepsis, or underlying liver disease. Neonatal jaundice that persists beyond 14 or 21 days always warrants investigation, even in breastfed babies. Unconjugated hyperbilirubinaemia in the neonatal period may be complicated by kernicterus (see later). The threshold for treat ing premature and lowbirthweight infants is lower due to their increased vulnerability to bilirubin neurotoxicity [7]. Jaundice may develop after the fourth day of life (early pattern) or towards the end of the first week of life (late pattern) and usually peaks around the end of the second week of life. The diagnosis is clinical: an exclusively breastfed infant with unconjugated hyperbilirubinaemia, normal conjugated bilirubin, haemoglobin and reticulo cyte counts, no maternal blood group incompatibility, and a normal physical examination except for jaundice. Characteristically, the firstborn is unaffected unless maternal sensitization with prior Rhpositive blood transfusion has occurred. The critical period is in the first few days when deeply jaundiced infants may develop kernicterus. This is a benign selflimited process although it is exaggerated in premature and lowbirthweight infants where it may persist for as long as 2 weeks. Urine contains both uro bilinogen and bilirubin, and stools are paler than normal. Factors contributing to prolonged physiological jaundice include delayed hepatic conjugation and bilirubin trans port, increased intestinal bilirubin absorption, reduced albuminbound bilirubin, particularly in premature infants, and other factors that depress liver function including hypoxia and hypoglycaemia. Serum bilirubin levels may be lower in infants with cir culatory failure, asphyxia, and sepsis. The Liver in the Neonate, in Infancy, and Childhood 591 Diagnosis may be suspected by antenatal examination of maternal blood for specific antibodies and confirmed by a positive Coombs test in the infant and blood typing of mother and child. Management with phototherapy, exchange transfusion, and phenobar bital has improved outcomes. Organic ani ons, which compete for bilirubin binding sites on albu min, increase kernicterus although the serum bilirubin level falls. Congenital haemolytic disorders these can lead to unconjugated hyperbilirubinaemia in the first 2 days of life. They include red cell enzyme defi ciencies (glucose6phosphate dehydrogenase and pyru vate kinase), congenital spherocytosis, and pyknocytosis.

These are measured in a moveable region of interest (red box) under Bmode ultrasound cholesterol medication how does it work buy atorlip-20 pills in toronto. Focused acoustic excitation (purple arrow and purple shaded areas) from an ultrasound probe result in shear wave propagation (green arrows) cholesterol levels over 600 cheap atorlip-20 20mg free shipping. The velocities are captured by highframe rate ultrasonography (blue lines) in a moveable region of interest under Bmode ultrasound (red circle) cholesterol test device home purchase cheap atorlip-20 on-line. A colour map (boxed area within ultrasound image) provides realtime shear wave data to assist in selecting a homogenous region of interest cholesterol medication diabetes buy 20 mg atorlip-20 amex. Source: Ultrasound elastography images courtesy of Dr Matteo Rosselli cholesterol levels european units purchase discount atorlip-20 on line, Dr Davide Roccarina cholesterol equivalent chart generic atorlip-20 20mg fast delivery, Associate Prof. However, the ability to select its position results in a lower failure rate, particularly in patients who are obese or who have ascites. This requires a very highframe 102 Chapter 7 rate ultrasound imaging sequence, typically over 1000 Hz [69]. All these methodologies require further validation before being considered for routine clinical practice. Molecular imaging Molecular imaging is an exciting field where a molecular probe, targeting a specific marker in a biological process (such as fibrogenesis), is administered and then detected in vivo using radiographic or nuclear medicine imaging techniques. This allows dynamic and quantitative assessment of fibrosis deposition or regression at a wholeliver level. The potential for molecular imaging is wide and may lead to a new understanding of the differing processes involved in chronic liver disease as well as their response to treatment. A major obstacle to the clinical application of such technology is the expense of both the probes and the equipment necessary for their detection. The shear waves are generated by a lowfrequency probe that is placed against the patient. It may be of particular use in diseases with a patchy distribution of fibrosis such as primary sclerosing cholangitis. Spleen stiffness measurement Quantification of spleen stiffness has emerged as a potential predictor of portal hypertension. Spleen stiffness may be measured applying any of the ultrasoundbased techniques used for liver stiffness. Ultrasound based elastography techniques also require specific calibration for the spleen due to higher baseline values [79]. Splenic stiffness is not used as a standalone test, but combined with other parameters. There have been promising results when splenic stiffness was combined with liver stiffness, liver stiffness plus Lok Index and Model Conclusions the advent of noninvasive testing in chronic liver diseases has altered the landscape of practice in hepatology. The rapid progress from their development to their inclusion in consensus guidelines has been remarkable. Noninvasive tests have evolved beyond their initial purpose to become prognostic indicators, risk stratification tools, and signposts for the initiation of treatment. Perhaps the most profound outcome of having these tests and techniques has been to change the understanding of the clinical course of patients with chronic liver diseases. The dynamic nature of hepatic fibrogenesis with its associated clinical manifestations has only really been appreciated in the noninvasive era. As with all investigations, the results of noninvasive tests should be carefully considered in the context of the individual patient, within the known limitations of the test and supported by published data. Beyond scoring: a modern interpretation of disease progression in chronic liver disease. Intraobserver and interobserver variation in the histopathological assessment of chronic viral hepatitis. Collagen proportionate area is superior to other histological methods for subclassifying cirrhosis and determining prognosis. Cost effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis C. Cost effectiveness of noninvasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation. Cirrhosis regression in hepatitis C patients with sustained virological response after antiviral therapy: a metaanalysis. Longitudinal assessment of liver stiffness in patients undergoing antiviral treatment for hepatitis C. Disadvantages of using the area under the receiver operating characteristic curve to assess imaging tests: a discussion and proposal for an alternative approach. Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C. Noninvasive diagnosis of nonalcoholic fatty liver and nonalcoholic steatohepatitis. Evaluation of a panel of noninvasive serum markers to differentiate mild from moderatetoadvanced liver fibrosis in chronic hepatitis C patients. Hepascore: an accurate validated predictor of liver fibrosis in chronic hepatitis C infection. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection. Diagnostic and 31 45 32 46 47 33 48 34 35 49 36 50 37 51 52 38 53 39 54 40 55 41 56 42 57 43 prognostic values of noninvasive predictors of portal hypertension in patients with alcoholic cirrhosis. Pitfalls of liver stiffness measurement: a 5year prospective study of 13,369 examinations. Liver stiffness is influenced by a standardized meal in patients with chronic hepatitis C virus at different stages of fibrotic evolution. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a metaanalysis of diagnostic accuracy. Performance of transient elastography for the staging of liver fibrosis: a metaanalysis. Ultrasoundbased transient elastography for the detection of hepatic fibrosis: systematic review and metaanalysis. FibroTest and FibroScan for the prediction of hepatitis Crelated fibrosis: a systematic review of diagnostic test accuracy. A liver stiffness measurementbased, noninvasive prediction model for highrisk esophageal varices in Bviral liver cirrhosis. Noninvasive Assessment of Fibrosis and Cirrhosis 105 58 Berzigotti A, Seijo S, Arena U et al. Elastography, 59 60 61 62 63 64 65 66 67 68 69 spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Liver stiffness is associated with risk of decompensation, liver cancer, and death in patients with chronic liver diseases: a systematic review and metaanalysis. Noninvasive tests for fibrosis and liver stiffness predict 5year outcomes of patients with chronic hepatitis C. Liver stiffness based optimization of hepatocellular carcinoma risk score in patients with chronic hepatitis B. Transient elastography based risk estimation of hepatitis B virusrelated occurrence of hepatocellular carcinoma: development and validation of a predictive model. Acoustic radiation force impulse imaging: in vivo demonstration of clinical feasibility. Acoustic radiation force impulse elastography for fibrosis evaluation in patients with chronic hepatitis C: an international multicenter study. Performance of acoustic radiation force impulse imaging for the staging of liver fibrosis: a pooled meta analysis. Quantitative viscoelasticity mapping of human liver using supersonic shear imaging: preliminary in vivo feasibility study. Accuracy of realtime shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B carriers: comparison of shearwave elastography and transient elastography with liver biopsy correlation. Realtime shearwave elastography: applicability, reliability and accuracy for clinically significant portal hypertension. Prospective comparison of spleen and liver stiffness by using shearwave and transient elastography for detection of portal hypertension in cirrhosis. Modified spleen stiffness measurement: a step forward, but still not the solution to all problems in the noninvasive assessment of cirrhotic patients. Accuracy of spleen stiffness measurement in detection of esophageal varices in patients with chronic liver disease: systematic review and metaanalysis. Utility of translocator protein (18 kDa) as a molecular imaging biomarker to monitor the progression of liver fibrosis. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven noninvasive laboratory tests. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Noninvasive elastographybased assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. In schistosomiasis, the ova excite a fibrous tissue reaction in the portal zones but this does not usually evolve into cirrhosis. Cirrhosis is defined as a diffuse disruption of the normal architecture of the liver with fibrosis and nodule formation. Clinically, patients may be asymptomatic (compensated) or clinically ill with jaundice, ascites, hepatic encephalopathy, or bleeding varices (decompensated). Life expectancy is reduced in cirrhotic patients and markedly reduced in the presence of decompensation. Many of the complications of cirrhosis are due to the development of portal hypertension, collateral and variceal formation, and the hyperdynamic circulation. There are significant secondary effects on the cardiac, pulmonary, and renal systems. The treatment of cirrhosis is directed at alleviating the underlying cause, for example abstinence from alcohol, antiviral therapy, weight loss, etc. Acute on chronic liver failure is a newly defined, clinically and pathophysiological distinct syndrome that commonly occurs in patients with cirrhosis and is characterized by acute deterioration in their clinical condition, occurrence of organ failures, systemic inflammation, and high shortterm mortality. Partial nodular transformation (or nodular regenerative hyperplasia) consists of nodules without fibrosis. Anatomical diagnosis the diagnosis of cirrhosis depends on demonstrating widespread nodules in the liver combined with fibrosis. Conversely, a nonfragmented core of liver without definite nodules may be obtained from a macronodular cirrhotic liver. Helpful diagnostic points in these circumstances include absence of portal tracts, abnormal vascular arrangements, hepatic arterioles not accompanied by portal veins, the presence of nodules with fibrous septa, and variability in cell size and appearance in different areas of the biopsy. In some cases it may be difficult to determine the aetiology as specific histological features may disappear with burntout cirrhosis. Suggested cofactors include age, sex, obesity, alcohol, iron intake, and other genetic factors as yet unknown. Similarly, many subjects drink excessive quantities of alcohol but only a small proportion ever develop cirrhosis. Progressive disease is more likely in patients with hepatitis B or C who drink excess alcohol. Patients heterozygous for 1 antitrypsin deficiency who are obese are more likely to manifest cirrhosis. The risk of developing cirrhosis may also depend on the age and sex of the patient, duration of the disease, Hepatic Cirrhosis 109 Table 8. If there are contraindications, such as ascites or a coagulation defect, the transjugular approach should be used. In many cases a diagnosis of cirrhosis can be made on the basis of a combination of clinical features and liver imaging, although imaging may miss early cirrhosis. Transient elastography (fibroscan) is a noninvasive method of evaluating liver fibrosis/cirrhosis. Ultrasound is not reliable for the diagnosis of cirrhosis but is useful for screening for hepatocellular carcinoma in patients with known cirrhosis, and for evaluating patency of the portal vein and the presence of ascites. Fatty change, focal liver lesions, ascites, collateral vessels, and splenomegaly may be identified. However, fibrosis may regress if the initiating insult is removed, for example hepatitis C, biliary obstruction, obesity, or iron overload. In most cases repeat liver biopsies have shown a lesser degree of fibrosis rather than a reversion to normal liver. Decompensation means cirrhosis with one or more of the following: ascites, bleeding Hepatic Cirrhosis 111 varices, hepatic encephalopathy, or jaundice. Hepatorenal syndrome, hyponatraemia, and spontaneous bacterial peritonitis are also features of decompensation but in these patients ascites invariably occurs first. Compensated patients have median survivals of 12 years compared to 2 years for decompensated patients [7].

It provides information on parenchymal infiltration and bile duct cholesterol levels meat chart atorlip-20 20 mg sale, portal vein grapefruit cholesterol medication interaction order 20 mg atorlip-20 visa, and hepatic artery involvement improve cholesterol levels quickly generic atorlip-20 20mg online. In autopsy studies percent of cholesterol in shrimp purchase atorlip-20 uk, local and distant metastases are found in about 50% of patients cholesterol test price philippines discount 20mg atorlip-20 free shipping. From what is known for other tumours cholesterol medication pictures atorlip-20 20mg on line, the data suggest that therapies in the future may be selected based upon the mutation pattern. Ultrasound showed dilated intrahepatic ducts, a hilar mass and a normal common bile duct. If nonsurgical drainage is to be performed, these appearances favour drainage of the left rather than the rightsided system. Contrast medium usually passes through the stricture(s) into dilated bile ducts above. The stricture is passed with a guidewire, brushings taken for cytology, and a stent placed. When right and left hepatic ducts are individually obstructed, puncture of both systems may be necessary for planning surgical intervention, but drainage of one lobe or sector is usually sufficient to relieve jaundice. Percutaneous cholangiography usually provides more information on tumour extension within the liver and biliary tree than endoscopic cholangiography. Intraductal ultrasonography, direct peroral cholangioscopy, and confocal laser endomicroscopy are emerging techniques. If the tumour is limited to the hepatic duct bifurcation with or without unilobar portal vein or hepatic artery involvement, then the lesion is usually resectable with an extended right or left hepatectomy. Portal vein embolization Extended right or left hepatectomy may result in postoperative hepatic insufficiency if the volume of the remnant liver is not adequate. Preoperative biliary drainage the role of preoperative biliary drainage prior to resection for hilar cholangiocarcinoma is controversial. However, malignant obstructive jaundice is associated with liver and kidney failure and coagulopathy, and many patients will benefit from preoperative biliary drainage. It should be considered in association with preoperative portal vein embolization when the future liver remnant is small. Laparoscopy the sensitivity of all the imaging modalities outlined above in detecting peritoneal disease is poor. Staging laparoscopy can reliably detect peritoneal disease and avoid unnecessary laparotomy in up to 30% of patients [28]. It is widely accepted that staging laparoscopy should be performed before laparotomy. Treatment Surgery Surgical resection is the primary treatment for cholangiocarcinomas. The challenge is to achieve tumournegative margins, and aggressive, extended resections including the portal vein may increase the likelihood of achieving this. However, these are highly complex operations and are best performed in specialist hepatobiliary surgical units. In inoperable patients, median survival after stent insertion depends upon the extent of the tumour. In patients with spread along the common bile duct, hepatic resection and pancreatoduodenectomy can be performed. Midbile duct cancers are resected with excision of the biliary tree and hilar lymphadenectomy. Hilar cholangiocarcinomas (Klatskin tumours) are resected by an extended right or left hepatectomy along with caudate lobectomy, excision of the biliary tree, and radical lymphadenectomy. Also, the mesh design of the metal stents allows side branches of the bile ducts to drain. The endoscopic route is successful in 90% of patients and in general has fewer complications than the percutaneous route, which is also effective but carries a higher risk of bleeding and bile leakage. Photodynamic therapy and radiofrequency ablation of malignant biliary strictures are novel techniques that have suggested a survival benefit in patients with unresectable cholangocarcinoma [35]. However, although early studies of photodynamic therapy [36,37] were promising, a subsequent larger study failed to confirm the benefits of these techniques [38]. Systemic chemotherapy with cisplatin and gemcitabine improves survival in unresectable disease. Surgical palliation Liver transplantation for intrahepatic cholangiocarcinoma is controversial because of poor results and at present this tumour is a contraindication to transplantation. Liver transplantation for hilar cholangiocarcinoma has evolved in the last decade and is now an accepted indication for transplantation in some centres. Such protocols to treat patients with cholangiocarcinoma are not generally used and are available in only a handful of highly specialized centres worldwide [34]. Surgical bypass is considered for those patients who have a good life expectancy and in whom stenting has failed [34]. In those patients unfit for surgery or with unresectable tumours, the goal of palliative treatment is relief of jaundice and itching and improvement of quality of life. Nonsurgical methods of biliary decompression include placement of stents across the stricture by the endoscopic or percutaneous route, and are preferable to elective surgical bypass. The anastomosis is between the jejunum and the third segment duct of the left lobe (arrow). Distal cholangiocarcinomas are more likely to be resectable than those at the hilum. If unresected, the 1year survival for cholangiocarcinoma is 50%, with 20% surviving at 2 years and 10% at 3 years. This reflects the observation that some tumours are slow growing and metastasize late. Periampullary and pancreatic neuroendocrine tumours are rare but important to recognize. The biological behaviour of these tumours is very different from that of adenocarcinomas, with a better prognosis. More than 70% of pancreatic neuroendocrine tumours present with metastatic disease (except insulinomas, which are benign in 90% of cases), but the overall 5year survival is 80%. Genetics and environmental predisposition In the majority of patients, there is no clear aetiological factor. The relatively low incidence of ampullary and periampullary cancers currently precludes accurate prospective data on outcomes. Critically, survival appears to be linked to these molecular markers, supporting the underlying hypothesis that for some ampullary cancers systemic therapy should be based on pancreatic cancer guidelines and some on colon cancer guidelines. As such, although the surgical and local therapies such as stenting should be similar to those for pancreas cancer, systemic therapies and prognostic variables should be linked to the underlying biology rather than the anatomy. Spread of the tumour Local tumour spread results in obstruction to the distal bile duct and obstructive jaundice, the most common presenting feature. The second part of the duodenum may also be invaded, resulting in ulceration of the mucosa and secondary haemorrhage. The splenic and portal veins may be invaded and may thrombose, with resultant splenomegaly. Involvement of regional nodes is found in approximately onethird of operated cases. Bloodborne metastases, with secondaries in the liver and lungs, follow invasion of the splenic or portal veins. The clinical picture is a composite one of cholestasis with pancreatic Other biliary malignancies Biliary cystadenocarcinoma and mixed hepatocellular and cholangiocarcinoma have been reported but are rare. Metastases at the hilum Cholestatic jaundice developing following the diagnosis of carcinoma elsewhere (in particular the breast and colon) may be due to diffuse metastases within the liver or duct obstruction by nodes at the hilum. If dilated bile ducts are shown and the patient is symptomatic with itching, biliary obstruction can be relieved by insertion of an endoprosthesis by the endoscopic or percutaneous approach [39]. Ampullary and periampullary carcinomas the region of the head of the pancreas is a common site for carcinomas causing malignant obstruction of the distal bile duct. Most arise in the head of the pancreas from the ductular epithelium, but may also develop from pancreatic acinar cells, the lining of the low bile duct, the ampulla of Vater (papilla), or rarely the duodenum. Resection is possible in 80% of patients with carcinoma of the ampulla compared with 20% for cancer of the head of the pancreas. In practice, the gallbladder is clinically apparent in only about half the patients, although at subsequent laparotomy a dilated gallbladder is found in threequarters. The spleen may be palpable if involvement of the splenic vein has caused thrombosis. Locoregional lymphatic metastases are common with ampullary and periampullary carcinomas [45]. Pancreatic cancers produce a prothrombotic tendency and may present with an episode of venous thrombosis or thrombophlebitis migrans. Investigations Blood biochemistry shows elevated serum bilirubin and alkaline phosphatase in keeping with cholestatic jaundice. Differential diagnosis Ampullary and periampullary carcinomas are difficult to diagnose in the early stages. The diagnosis must be considered in any patient over 40 years of age with progressive or intermittent jaundice. The suspicion is strengthened by persistent or unexplained abdominal pain, weakness and weight loss, diarrhoea, glycosuria, positive faecal occult blood, hepatomegaly, a palpable spleen, or thrombophlebitis migrans. It is important to exclude local and distant spread of tumour and to determine potential resectability for planning treatment. There are no universally accepted criteria for defining resectability in ampullary and periampullary adenocarcinomas, but most centres consider local vascular invasion as locally advanced disease and unresectable. Jaundice is of gradual onset, usually progressive, but ampullary neoplasms can cause mild and intermittent jaundice. Itching is a common but not invariable feature, and when present comes after jaundice. Pain is often worse at night, sometimes ameliorated by crouching or leaning forward, and may be aggravated by eating. Ulceration of the duodenum can result in haematemesis or, more commonly, occult blood loss. Obstruction of the duct may also lead to pancreatic insufficiency, causing diarrhoea. Malignant Biliary Diseases 303 Ultrasound is often the initial investigation in a jaundiced patient. It may show a dilated bile duct down to the pancreas, but has low sensitivity in detecting ampullary and periampullary tumour masses. It can be useful in selected cases for detecting small tumours and invasion of major vascular structures [49]. There is a sheet of benign biliary epithelial cells and above this a small group of large polymorphic cells characteristic of adenocarcinoma. Routine preoperative biliary drainage increases morbidity and is not required in patients with resectable ampullary and periampullary cancers. Liver and peritoneal metastases and spread to adjacent organs can be visualized and biopsies taken during laparoscopy [50]. Treatment Resection Patients with ampullary carcinoma who undergo potentially curative resection have a 5year survival between 40 and 70% [51]. This operation was modified in 1978 to preserve antral and pyloric function (pyloruspreserving pancreaticoduodenectomy). Both techniques are equally effective with equivalent longterm survival and quality of life [54]. Following resection, reconstruction involves anastomosis of the remaining pancreas, distal bile duct, and stomach to the small intestine. Both methods have comparable incidence of pancreatic fistula, the most feared complication after pancreaticoduodenectomy, and have a similar overall postoperative complication rate [55]. Pancreaticojejunostomy is commonly performed by anastomosis of the pancreatic duct to the jejunal mucosa, although some surgeons prefer to invaginate the pancreatic stump into the jejunum. Pancreaticogastrostomy involves anastomosis of the pancreatic stump to the posterior wall of the stomach. Extended pancreatoduodenectomy, which involves a more extensive resection to remove retroperitoneal lymph nodes and clearance of soft tissue around the pancreas, increases postoperative morbidity without improving longterm survival [56]. Every attempt should be made to obtain a tumourfree margin and frozen section examination of the pancreatic resection margin is commonly performed by most surgeons during surgery to ensure a negative margin.

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Longterm benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis cholesterol risk ratio chart discount atorlip-20 online visa. A pilot study of 2 years of interferon treatment in patients with chronic delta hepatitis foods for high cholesterol diet buy atorlip-20 with visa. Pegylated interferon alpha2b as monotherapy or in combination with ribavirin in chronic hepatitis delta cholesterol medication uses order atorlip-20 20mg with mastercard. Efficacy of interferon alpha2b and lamivudine combination treatment in comparison to interferon alpha2b alone in chronic delta hepatitis: a randomized trial cholesterol levels nz normal range buy cheap atorlip-20. Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon cholesterol levels range australia discount 20 mg atorlip-20 overnight delivery. Nucleos(t) ide analog(s) prophylaxis after hepatitis B immunoglobulin withdrawal against hepatitis B and D recurrence after liver transplantation cholesterol test how accurate purchase cheap atorlip-20 line. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proofofconcept randomized, double blind, placebocontrolled phase 2A trial. The current standard of care for hepatitis C using a combination of directacting antiviral agents results in sustained virological response rates of 95% in most patients. The risk of hepatocellular carcinoma remains after hepatitis C virus cure in patients with cirrhosis. Epidemiology Hepatitis C is one of the 10 leading causes of infectious disease deaths worldwide and a leading cause of liver related deaths, causing over 670 000 deaths per annum [2,3]. The highest prevalence has been reported from Africa (Egypt) and Asia, with a somewhat lower prevalence in industrialized countries in the West, although in countries such as Japan (2. Considerable progress has been made in our understanding of hepatitis C since its discovery in 1989. Until screening of blood donors was introduced, hepatitis C accounted for most posttransfusion nonA, nonB hepatitis. Perinatal and sexual transmission can occur, and inhaled drug use can also result in transmission. Nosocomial outbreaks of hepatitis C have been reported after lapses in infection control practices via unsafe injections, in dialysis units, via invasive procedures, and more recently by diversion of opioid medications for injection. The safety of blood transfusions has increased, but not all countries test blood for hepatitis C. Translation is mediated by an internal ribosome entry site in the 5 untranslated region. Two glycoprotein products, E1 or gp35 and E2 or gp70, are found in the viral envelope. There are hypervariable regions, particularly in the E1 and E2 domains; these regions may be important antigenic sites and their variability may be important in persistence of infection and immunopathogenesis. Divergence may be enhanced by the induction of neutralizing antibodies targeted to the envelope proteins. After cleavage, non structural proteins remain associated with cellular membranes (the membranous web), forming a replication complex. Claudin1 (a tight junction component) has been shown to be an important coreceptor [13]. Chronic hepatitis C infection is associated with lipid accumulation in hepatocytes. The virus includes lipoprotein fractions in its envelope, a prerequisite for infection. A proportion of patients with chronic hepatitis C suffer from diabetes and steatosis [16]. There is an effect of viral mutation on Tcell recognition so that immune escape mutations may favour persistence of the virus. Antibody responses occur that may neutralize viral proteins but escape mutants that evade Bcell responses can be selected. Fibrosis in chronic hepatitis C infection occurs because of the activation of hepatic stellate cells by cytokines and other signalling molecules induced by the inflammatory process. The resulting innate antiviral response is an early response against virus infection. Fibrosis begins around the portal tracts and gradually extends into the lobules towards the central veins. Epidemiological differences in age distribution of major types and the risk factors associated with particular genotypes have become apparent. Type 4 infection is the most prevalent infection in Egypt and many parts of the Middle East and Africa. Genotype 5 was thought to be confined to South Africa but pockets have been found in France, Spain, Syria, and Belgium. Type 6 is prevalent in SouthEast Asia and in Asian Americans and Asian Australians. Third generation immunoassays include antigens from the nucleocapsid (C22) and other nonstructural regions of the genome. The reticulin framework of the liver is usually well preserved, except in some cases of massive and submassive necrosis. Management Early identification of acute hepatitis C is important, but may be difficult as the disease is usually silent; 75% of patients are not jaundiced and have nonspecific symptoms. Management of acute sporadic hepatitis C includes conventional supportive treatment or specific antiviral therapy. However, asymptomatic patients could be treated immediately as they appear to have a higher risk of chronic disease than those who present with acute symptomatic disease, are infectious, and could be lost to followup. The mean incubation period of hepatitis C, defined as the time from exposure to the onset of symptoms, ranges from 2 to 12 weeks (average 7 weeks). Symptoms during the acute phase are non specific and may include fatigue, lethargy, anorexia, and right hypochondrial discomfort. Perhaps 25% of cases are icteric; patients with jaundice are more likely to clear the virus. Female gender and icteric hepatitis are associated with a higher chance of viral clearance. Pathology Most patients with welldocumented acute hepatitis C do not require a liver biopsy. Natural history the onset of chronic hepatitis C is often insidious and usually has gone unnoticed by the patient. Variability in rates of progression of the disease makes the prediction of ultimate outcome difficult. Several host, viral, and environmental factors influence the rate of progression to cirrhosis. Progression to cirrhosis is infrequent in children and endstage liver disease during childhood is rare [32,33]. A subset of patients with chronic hepatitis C may test positive for liver kidney microsomal1 antibody. Mixed cryoglobulinaemia caused by Blymphocyte expansion may cause a systemic vasculitis and multiple organ damage. Patients with hepatitis C have an increased prevalence of insulin resistance and type 2 diabetes mellitus. There may be a direct genotype association (steatosis is more common in patients with genotype 3) that influences this metabolic effect [38]. Typically, patients with chronic hepatitis C have mild portal tract inflammation with lymphoid aggregates or follicles and mild periportal piecemeal necrosis. Although many of the lymphoid follicles are associated with bile ducts, ductopenia is not observed. A positive correlation has been documented between serum hepcidin levels and both necroinflammation and fibrosis [40]. Management Evaluation of liver disease Treatment of hepatitis C has improved considerably over the last 10 years. If the test is positive, serum aminotransferases, bilirubin, alkaline phosphatase, and prothrombin time should be measured to assess hepatic function and platelet count to assess for portal hypertension. Physicians should vaccinate patients with chronic hepatitis C against hepatitis A and B. Liver biopsy and assessment of fibrosis A liver biopsy is helpful in grading the degree of inflammation and staging the degree of fibrosis. Earlier guidelines recommended antiviral therapy for those patients with chronic hepatitis C who have advanced stages of fibrosis. These indices have been validated in identifying patients with advanced fibrosis or cirrhosis but they are not accurate in differentiating different stages of fibrosis; some patients fall into the indeterminate zone and additional tests are needed to determine the stage of disease. Liver fibrosis can also be assessed by elastography, which measures the speed of propagation of a shear wave in the liver. Other factors, such as inflammation and congestion in the liver, can contribute 444 Chapter 23 to tissue elasticity. A strong relationship between liver stiffness and the hepatic venous pressure gradient has been described [40]. When an acoustic pulse displaces the tissue residing in its path, shear waves are generated; an increase in shear wave velocity correlates closely with increasing tissue stiffness. The diagnostic performance and clinical use of noninvasive markers of hepatic fibrosis have recently been compiled [42]. Noninvasive tests are essential in patients with bleeding disorders (haemophilia) and hepatitis C. Elastography is less widely available, and more expensive, requiring capital outlay and trained operators. Transient elastography is better at ruling out cirrhosis than ruling in cirrhosis. General management hepatitis C should be advised to minimize their intake of alcohol and not to donate blood, tissue, or organs. Indications for treatment All patients, irrespective of the degree of fibrosis, are potential candidates for treatment. Adolescents >12 years or weighing >35 kg can be treated with sofosbuvir and ledipasvir. There is evidence that alcohol and hepatitis C may synergistically aggravate hepatic injury, although the safe limits of alcohol consumption have not been established. The drug exerts its action after intracellular phosphorylation to mono, di, and triphosphate nucleotides. Patients with genotype 1 or 4 are treated for 12 months whereas patients with genotype 2 or 3 are treated for 6 months. There are rare reports of bone marrow suppression resulting in bone marrow aplasia. Headaches, poor appetite, weight loss, increased need for sleep, psychological effects (irritability, anxiety, depression), hair loss, thrombocytopenia, and leucopenia are also common sideeffects. Unusual or severe sideeffects include seizures, acute psychosis, bacterial infections, autoimmune reactions, and thyroid disease. Hyperthyroidism or thyroiditis is relatively common and can be seen in up to 5% of patients, particularly in those with preexisting antithyroid antibodies. Patients require education on the importance of adherence to treatment, and on the potential effect of overthecounter medications. Nonnucleosides interact with the polymerase outside the catalytic site, producing allosteric changes that compromise its function. At least five different sites (named A, B, C, D, and E) have been shown to be targeted by nonnucleoside inhibitors. As nonnucleoside inhibitors are allosteric blockers, different resistance patterns are observed. Polymerase inhibitors tend to work across genotypes; nucleoside inhibitors have a high barrier to resistance. However, 1a versus 1b subtype profiling of polymerase inhibitors that bind at the known nonnucleoside binding sites has shown that inhibition might vary. Drugs that are potent Pglycoprotein inducers can reduce sofosbuvir blood concentrations and thus potentially lessen the therapeutic effect. Patients should not receive the antiarrhythmic amiodarone with sofosbuvirbased regimens owing to the risk of lifethreatening arrhythmias. Because of the long halflife of amiodarone, an interaction can occur months after its discontinuation. One tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir is taken daily.