Raghu Seethala, MD

• Department of Emergency Medicine
• Mount Sinai School of Medicine
• New York, New York

Long recognized as an important cause of diarrhea in animals antibiotics for bladder infection during pregnancy purchase genuine tinidazole on-line, cryptosporidia were not identified as causes of human enteritis until 1976 bacteria yogurt purchase tinidazole 300mg overnight delivery, when first observed in a patient with a congenital IgA immunodeficiency antibiotics for uti in pregnancy cheap tinidazole 1000mg with visa. Of 20 species and genotypes that infect humans virus asthma buy tinidazole online pills, the most common are zoonotic species infection vaginal discharge purchase tinidazole 300mg on-line, Cryptosporidium parvum and a species antibiotic side effects order genuine tinidazole online, Cryptosporidium hominis, that only infects humans. The former is more likely to be encountered in rural populations, whereas the latter dominates in urban settings. The organisms appear as small spherical structures arranged in rows along the microvilli of the epithelial cells. Although they remain external to the cytoplasm of the intestinal epithelial cell, they are clearly enveloped by a membrane of host cell origin. Oocysts shed into the intestinal lumen contain four sporozoites that are not contained within sporocyst structures like their relative, Toxoplasma. Their cell wall provides the unusual property of acid-fastness, allowing them to be visualized with stains generally employed for mycobacteria. Unlike those of Toxoplasma, cryptosporidia oocysts are fully mature and immediately infective to the next host on passage in the feces. After ingestion by another animal, sporozoites are released from the oocyst and attach to the microvilli of the small intestinal epithelial cells, where they are transformed into trophozoites. These divide asexually by multiple fission (schizogony) to form schizonts containing eight daughter cells known as type 1 merozoites. On release from the schizont, each daughter cell attaches itself to another epithelial cell, where it repeats the schizogony cycle, producing another generation of type 1 merozoites. In the absence of effective immunity, this phase may constitute an autoinfective portion of the life cycle allowing perpetuation of the infection. These merozoites are destined to invade intestinal cells and give rise to male (microgametocyte) and female (macrogametocyte) sexual forms. Gamete development ensues and after fertilization, the resulting zygote develops into an oocyst that is shed into the lumen of the bowel. The majority, approximately 80%, possesses a thick protective cell wall that ensures their intact passage in the feces and survival in the external environment. The cell membrane ruptures, releasing infective sporozoites directly into the intestinal lumen and initiating a new "autoinfective" cycle within the original host. In the normal host, the presence of innate or acquired immunity dampens both the cyclic production of type 1 merozoites and the formation of thin-walled oocysts, halting further parasite multiplication and terminating the acute infection. In the immunocompromised, both presumably continue, explaining why such individuals develop severe, persistent infections in the absence of external reinfection. Experimental and epidemiologic data suggest that domestic animals constitute an important reservoir of disease in humans. Outbreaks of human disease in day care centers, swimming pools, hospitals, and urban family groups indicate that most human infections result from person-to-person transmission. In Western countries, between 1% and 4% of small children presenting to medical centers with gastroenteritis have been shown to harbor cryptosporidia oocysts. In some outbreaks of diarrhea in day care centers, most attendees were found to have oocysts in their stool. Infection rates of cryptosporidiosis in adults suffering from gastroenteritis is approximately one-third of that reported in children; it has been highest in family members of infected children, medical personnel caring for patients with cryptosporidiosis, male homosexuals, and travelers to foreign countries. Because of the advent of antiretroviral therapies, this has been reduced to 1% to 2%; in Haiti and Africa, high percentages of such individuals who do not have access to antiretroviral therapies may be involved. In many developing countries, most children may acquire multiple infections with Cryptosporidium before the age of 5 years. After that infections can still be detected, but symptoms may be absent suggesting that constant exposure may help maintain a measure of immunity. Most noteworthy was the outbreak involving municipal water in the city of Milwaukee in 1993. The hardy nature of the oocysts, which do not respond to conventional chlorine treatment of water and many other commonly used disinfectants, makes it likely that there is also indirect transmission via contaminated food and fomites. By light microscopy, bowel changes appear minimal, consisting of mild-tomoderate villous atrophy, crypt enlargement, and a mononuclear infiltrate of the lamina propria. Indirect evidence suggests that antibodies in the intestinal lumen exert a protective effect against initial C parvum infection. Occasionally, purging, accompanied by a mild malabsorption and weight loss, continues for up to 1 month. Except for its shorter duration, more prominent abdominal pain, and relative lack of flatulence, the clinical manifestations of cryptosporidiosis closely resemble those produced by Giardia lamblia. Radiographic and endoscopic examinations of the gut are either normal or demonstrate mild, nonspecific abnormalities. In such patients, cryptosporidiosis is usually indolent at onset, and manifestations are like those seen in normal hosts, but the diarrhea is more severe. Patients with biliary cryptosporidiosis present with typical manifestations of cholecystitis and cholangitis. Although other intercurrent infections are usually the direct cause of death, malnutrition and complications of parenteral nutrition contribute. Oocyst excretion is most intense during the first week of illness, tapers during the second week, and generally stops with the cessation of diarrhea. When direct examinations are negative, concentration procedures are used and the concentrate restained. In the immunocompromised host, the severity and chronicity of the diarrhea warrant therapeutic intervention. Unfortunately, there is no uniformly effective anticryptosporidial agent available now. Paromomycin, a luminal antimicrobial, has been shown to reduce the intensity of diarrhea in some patients, and parenteral octreotide acetate, a somatostatin analog, has been useful in decreasing stool volumes. The only uniformly successful approach has been the reversal of underlying immunologic abnormalities. When appropriate, withdrawal of cancer chemotherapy agents or immunosuppressive drugs may result in a cure. Stool precautions should be instituted at the time the diagnosis is first suspected; for the immunosuppressed patient, this should be whenever diarrhea, regardless of the presumed cause, is first noted. This is particularly important in cancer chemotherapy and transplantation units, where spread of the disease from a symptomatic patient to other immunosuppressed patients can have lifethreatening consequences. Oocysts can survive for many months in the external environment and have been found in most water sources across the United States. The species name has been derived from the University in Lima, Peru, where much initial work was done on this parasite. This parasite gained notoriety because of foodborne outbreaks of illness that were ultimately linked to raspberries imported into the United States. Humans appear to be the only host for this parasite and its normal endemicity is usually linked to underdeveloped countries. The parasite has an oocyst that measures 8 to 10 m in diameter and stains acid-fast variable. A big difference between the two is that it takes a week or longer for the oocyst to complete sporulation outside the host. Complete sporulation results in an oocyst with two sporocysts each containing two sporozoites. Where both parasites are present in populations, Cryptosporidium has both a greater incidence and prevalence. Isospora belli, now named Cystoisospora belli, is another protozoan closely related to Toxoplasma. This parasite has a worldwide distribution in subtropical areas, but is not that prevalent. Side-by-side comparison of staining and size differences between Cryptosporidium and Cyclospora. Once classified among the Protozoa they are now known to be fungi and are placed in their own phylum, the Microspora. As the name implies, this group of organisms is characterized by producing small spores. There are over 1200 known species parasitizing a very wide variety of eukaryotic hosts. There have, however, been reports of infections caused by these organisms in children of certain African countries. The principal ones of concern are Enterocytozoon bieneusi and three different species of Encephalitozoon. Infections begin by the ingestion of spores that discharge a polar filament in the environment of the small intestine. Sporoplasm containing a nucleus travels through this polar filament into host cells that have been punctured. The easiest way to diagnose these infections is from stained clinical smears, especially of fecal samples. Albendazole has proven useful against disseminated microsporidiosis and a combination of fumagillin drops and albendazole is recommended for ocular infections. Fecal smear stained both with modified acid-fast and trichrome stains and showing and Isospora oocyst (large) and microsporidian spores (small). On advice of his physician, he took oral chloroquine prophylaxis beginning 1 week before departure and ending 1 week after his return. The duration of these symptoms has been about 8 hours, ending with profuse sweating, only to recur again within 48 hours. Laboratory studies reveal only a mild anemia, with a platelet count of 100 000/mm3 (normal 200 000-400 000). In some malarial infections, treatment to prevent relapse (by destroying persistent hepatic schizonts) is necessary in which two of the following After primary infection, T gondii may persist as cyst forms in all of the following tissues except which of the following: A. Because of their divergent organization and medical importance, they are considered in separate chapters. The amebas are characterized by movement involving cytoplasmic streaming dependent upon pseudopodia formation. These projections of the relatively solid ectoplasm are formed by streaming of the inner, more liquid endoplasm. They move the ameba forward and, incidentally, engulf and internalize food sources found in its path. Most amebas, when faced with a hostile environment, can produce an external cyst wall that surrounds and protects them. These cysts may survive for prolonged periods under conditions that would rapidly destroy the motile trophozoite. They are widely distributed in nature, being found in literally all bodies of standing fresh water. Few free-living amebas produce human disease, although two genera, Naegleria and Acanthamoeba, have been implicated occasionally as causes of meningoencephalitis and keratitis. Most amebas are amitochondriate, presumably because of the anaerobic conditions under which they exist in the colon. Only one, Entamoeba histolytica, regularly produces disease; it has been recently subdivided into two morphologically identical but genetically distinct species, an invasive pathogen that retains the species appellation "histolytica" and a commensal organism, now designated Entamoeba dispar. Amebiasis is found worldwide and is caused by the potentially pathogenic E histolytica. Approximately 10% of patients with this parasite will have gastrointestinal symptoms and 1% will experience extraintestinal disease which can be life-threatening. Occasionally, severe dysentery with abdominal cramping and a high fever can occur. Entamoeba dispar, which is morphologically identical to E histolytica, accounts for the vast majority of E histolytica-like infections. Close to 500 million people are thought to be infected at any one time, but most of these are likely due to the morphologically identical E dispar. Because methods are now available to distinguish E histolytica from E dispar, the figure of 500 million infected with E histolytica may actually be closer to 50 million. Transmission from person to person occurs when a cyst passed in the stool of one host is ingested directly or indirectly, such as through food or water, by another. Although the average infective dose exceeds 1000 organisms, ingestion of a single cyst has been known to produce infection. After passage through the stomach, the cyst eventually reaches the distal small bowel. Here, the cyst wall disintegrates, releasing the quadrinucleate parasite, which divides to form eight small trophozoites that are carried to the colon. Colonization is most intense in areas of fecal stasis such as the cecum and rectosigmoid, but may be found throughout the large bowel. The trophozoites are microaerophilic, dwell in the lumen or wall of the colon, feed on bacteria and tissue cells, and multiply rapidly in the anaerobic environment of the gut. Even though they are called amitochondriate, they do possess nuclear-encoded mitochondrial genes and a remnant organelle.

Recent clinical trials of enzyme replacement therapy infection 7 weeks after abortion order 1000 mg tinidazole with mastercard, sebelipase alpha antimicrobial and antibacterial order tinidazole 1000 mg mastercard, resulted in improved lipid profile and reduced transaminases [157]; longterm outcomes are awaited antibiotics during labor 300mg tinidazole amex. Mucopolysaccharidoses Deficiency of lysosomal acid lipase is a rare and reces sively inherited condition antibiotic eye ointment for dogs purchase tinidazole on line, in which increased cholesterol these are due to deficiencies of enzymes involved in degradation of glycosaminoglycans bacteria news articles order 300mg tinidazole otc. Many variants are described and although hepatosplenomegaly is a feature infection wisdom tooth extraction cheap tinidazole 300 mg fast delivery, liver disease is not associated. Hurler syndrome (gargoylism) has autosomal recessive inheritance and is characterized by deficiency of lidu ronidase, a lysosomal degradation enzyme. Key features the Liver in the Neonate, in Infancy, and Childhood 613 include coarse facial features, dwarfism, limitation of joint movement, deafness, abdominal hernias, hepatos plenomegaly, cardiac abnormalities, and mental retardation. Electron microscopy shows characteristic membrane bound inclusions in hepatocytes and Kupffer cells. This lysosomal storage material disappears in the majority of patients after bone marrow transplantation [158]. Diagnosis may be made by finding increased urinary glycosaminoglycans and confirmed by enzyme activity assays in serum, leukocytes, and cultured skin fibroblasts. Hypercholesterolaemia is controlled by reduction in dietary saturated fats and administration of bile acid sequestrants such as cholestyramine or apheresis [160]. Preemp tive liver transplant prior to the onset of severe vascular disease may be curative for homozygotes [162]. Oesophageal or rectal varices develop inevitably with increasing hepatic fibrosis and portal hypertension. The use of propranolol or band ligation as prophy lactic therapy remains unproven in children. Treatment with appropriate broadspectrum antibi otics, such as piperacillin with clavulanic acid (60 mg/kg tds), are useful firstline drugs until bacterial cultures are positive. Salt and water retention leading to ascites and cardiac failure should be effectively managed with diuretics and salt and water restriction. Chronic encephalopathy is difficult to detect in chil dren, but may present with regression in school work, lack of energy, and drowsiness. It is best treated with lactulose and nonabsorbable antibiotics including rifaximin. Liver transplantation Cirrhosis and portal hypertension Any form of paediatric chronic or metabolic liver disease may lead to cirrhosis and portal hypertension. Cardiac cirrhosis is unusual in childhood unless secondary to constrictive pericarditis. Hepatic decompensation is marked by diminished hepatic synthetic function and complications such as malnutrition, bleeding oesophageal varices, ascites, encephalopathy, and hepatorenal failure. The clinical features include palmar and plantar erythema, telangiec tasia, malnutrition, hypotonia, and hepatosplenomegaly with ascites. Management includes nutritional support (see ear lier) and prevention of complications. Indications the indications for liver transplantation include acute or chronic liver failure, metabolic liver disease or inborn errors of metabolism with extrahepatic sequelae, and unresectable liver tumours. Over the last 20 years, the success of paediatric liver transplantation has altered the prognosis for many infants and children. The main fac tors in improving survival in childhood include advances in preoperative management such as treatment of com plications and nutritional support. The developments in innovative surgical techniques to expand the donor pool have extended liver transplantation to the neonatal age group, while improvements in postoperative manage ment including immunosuppression have led to increased survival and improved quality of life. Biliary atresia remains the commonest 614 Chapter 31 indication under the age of 5 years [88]. The indications for liver transplantation for children with acute liver failure depend on the aetiology and multisystemic involvement. Liver transplantation is con traindicated for children who have evidence of multisys tem involvement. Inborn errors of metabolism Liver transplantation is indicated for inborn errors of metabolism if the hepatic enzyme deficiency leads to irreversible liver disease, liver failure and/or hepatoma. Indications for transplantation for liver tumours include either unresectable benign tumours causing hepatic dysfunction or unresectable malignant tumours without evidence of extrahepatic metastases [167]. Surgical approach, immunosuppressive regimens, and outcome Due to organ donor shortage, most children will receive a split liver transplant or live related graft. Postoperative management and immunosuppression are similar to adults (Chapter 37). Most children now receive induc tion immunosuppression with monoclonal antibodies against the interleukin2 receptor, tacrolimus with or without steroids, and mycophenolate mofetil. Hirsutism and gingival hyperplasia, which are wellknown side effects of ciclo sporin, have an important effect on quality of life, par ticularly in adolescents. The prevention of nephrotoxicity from calcineurin inhibitors needs careful monitoring of immunosuppressive levels to minimize this longterm effect, and transfer to renalsparing agents such as siroli mus or mycophenolate mofetil [168]. Children who survive the initial 3month posttrans plant period without major complications should achieve a normal lifestyle, despite the necessity for continuous immunosuppressive monitoring. Prospective studies have indicated a rapid return to normal nutritional status in over 80% of children within 1 year posttransplant. Linear growth may be delayed between 6 and 24 months posttransplant, which is directly related to corticoster oid dosage and preoperative malnutrition. Early studies of neuropsychological development dem onstrated that the rate of improvement posttransplant is related to the extent of motor or psychological devel opmental delay pretransplant, thus highlighting the necessity for early transplantation, particularly for infants with chronic liver disease [169]. Prospective studies show an initial deterioration in psychosocial development posttransplant, which may be related to prolonged hospitalization, and stress of the transplant operation [170]. Longterm studies have shown that chil dren surviving liver transplantation enter puberty nor mally, girls will develop menarche, and both boys and girls will have pubertal growth spurts. Noncompliance with immunosuppressive therapy is a significant problem in adolescents and a major cause of graft loss [171]. Tumours of the liver (see also Chapters 35 and 36) Primary tumours in infants and children are rare; two thirds are diagnosed before the second year of life. Secondary tumours are extremely rare and are usually associated with neuroblastoma of the adrenals. The site and extent of tumour must be defined by crosssectional imaging and, if necessary, angiography. Hamartomas these benign, congenital lesions present as an abdomi nal mass in the first 2 years of life. They may be an the Liver in the Neonate, in Infancy, and Childhood 615 incidental finding at autopsy and must be distinguished from malignant tumours. They consist of abnormal arrangements of all the cells of the normal liver, particu larly bile ducts and fibroblasts. Mesenchymal hamartoma this is a rare developmental anomaly, largely of bile ducts, seen in children less than 2 years old. They should be treated conservatively but require monitoring as a small subset become malignant. Tumours are classified as: fetal, embryonal, mac rotrabecular, and smallcell undifferentiated. Children usually present with an enlarged liver and a grossly ele vated fetoprotein. Other associations include: hemihy pertrophy, Wilms tumour, precocious puberty, and familial adenomatous polyposis. The prognosis is now excellent with a combination of chemotherapy, surgery, or liver transplantation [167]. The patients present with weight loss, abdominal swelling in the right upper quadrant, pain, ascites, and jaundice. The fibrolamel lar form has a much better prognosis and is often resect able [172]. Transplantation is sometimes indicated in small tumours with no extrahepatic spread. Infantile haemangioendothelioma This, usually benign, vascular tumour of infancy con sists of endotheliumlined channels of capillary size. Severe anaemia and thrombocytopenia have been attributed to intralesional microangiopathic hae molysis [173]. Treatment includes managing cardiac failure, and hepatic arterial embolization for refractory heart failure. Fetal bile acid metabolism during infancy: analysis of 1 beta hydroxylated bile acids in urine, meconium and feces. Comparison of the effectiveness of phototherapy and exchange transfusion in the management of nonhemolytic neonatal hyperbilirubinemia. The global prevalence of glucose6phosphate dehydrogenase deficiency: a systematic review and metaanalysis. Population screening for neonatal liver disease: potential for a communitybased programme. The diagnostic and therapeutic role of endoscopic retrograde cholangiopancreatography in children. Parvovirus B19 as a possible causative agent of fulminant liver failure and associated aplastic anemia. Neonatal varicella frequently associated with visceral complications: a retrospective analysis. Histopathologic features of the liver in pediatric acquired immune 24 25 26 27 28 29 30 31 32 33 34 35 36 37 deficiency syndrome. Clinical features and prognosis of children assessed for isolated small bowel or combined small bowel and liver transplantation. Alpha1antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease associated protein aggregates. Single nucleotide polymorphismmediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of endstage liver disease in alpha1antitrypsin deficiency. Alpha1 antitrypsin deficiencyassociated liver disease progresses slowly in some children. Prognosis of alpha1antitrypsin deficiencyrelated liver disease in the era of paediatric liver transplantation. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Visual loss and idiopathic intracranial hypertension in children with Alagille syndrome. Early life predictive markers of liver disease outcome in an International, Multicentre Cohort of children with Alagille syndrome. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Biliary diversion for progressive familial intrahepatic 53 54 55 56 57 58 59 60 61 62 63 64 65 cholestasis: improved liver morphology and bile acid profile. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Resolution of liver biopsy alterations in three siblings with bile acid treatment of an inborn error of bile acid metabolism (delta 43oxosteroid 5 betareductase deficiency). Mutations in the gene encoding peroxisomal alphamethylacyl CoA racemase cause adultonset sensory motor neuropathy. The metabolism of 3alpha, 7alpha, 12alpha trihydorxy5betacholestan26oic acid in two siblings with cholestasis due to intrahepatic bile duct anomalies. Delta 43oxosteroid 5 betareductase deficiency: failure of ursodeoxycholic acid treatment and response to chenodeoxycholic acid plus cholic acid. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective longterm therapy. A mutation in the human canalicular multispecific organic anion transporter gene causes the DubinJohnson syndrome. Claudin1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease. Severe congenital anomalies requiring transplantation in children with Kabuki syndrome. The biliary atresia splenic malformation syndrome: a 28year singlecenter retrospective study. The next challenge in pediatric cholestasis: deciphering the pathogenesis of biliary atresia. Biliary atresia in England and Wales: results of centralization and new benchmark. Five and 10year survival rates after surgery for biliary atresia: a report from the Japanese Biliary Atresia Registry. Histologic study of biliary fibrous remnants in 48 cases of extrahepatic biliary atresia: correlation with postoperative bile flow restoration. Does the morphology of the extrahepatic biliary remnants in biliary atresia influence survival Outcome in adulthood of biliary atresia: a study of 63 patients who survived for over 20 years with their native liver.

Airway protection with orotracheal intubation should be provided in unconscious patients or those with severe haemorrhage (haematemesis) before endoscopy to pre vent airway aspiration antibiotics for face cyst discount 300 mg tinidazole with amex. However bacteria notes buy discount tinidazole 300mg online, this should be done cautiously as volume expansion increases splanchnic blood flow and portal pressure bacterial lawn discount tinidazole 300mg amex, as hypovolaemic shock causes reflex splanchnic vasoconstriction zinc antibiotic resistance discount 1000 mg tinidazole otc. Administration of vasoac tive drugs from admission (see later) helps maintain haemodynamic stability without the need for excessive volume expansion bacteria nitrogen cycle generic tinidazole 1000 mg on-line. Packed red blood cells should be transfused restrictively (target haemoglobin level ~7 g/dL) antibiotic resistance leadership group generic tinidazole 500mg with mastercard, because a less restrictive policy (target haemoglobin ~9 g/dL) may increase mortality [78]. Such restriction does not apply to patients in Child class C, to cases with massive haemorrhage, or to patients with a history of ischaemic cardiovascular disease. It is increasingly evident that therapy can be tailored according to prognostic factors, such as the degree of liver failure or concomitant disor ders. Vasoactive drugs Hypovolaemic shock enhances bacterial translocation and the incidence of sepsis. Also, variceal bleeding (together with diagnostic and therapeutic endoscopy) carries a high risk of aspiration pneumonia. Because of this, prophylactic antibiotics should be started on admis sion to prevent the occurrence of infections and improve survival [55]. The Baveno Consensus Workshop recom mended the use of intravenous ceftriaxone at 1 g/24 h in patients with advanced cirrhosis, in areas with high prevalence of quinoloneresistant bacterial infections, and in patients on previous quinolone prophylaxis, but the choice of the ideal antimicrobial prophylaxis should be made in each centre depending on the local pattern of antibiotic resistances. All these drugs are used interchangeably as they are considered equally effective in controlling the bleeding and preventing rebleeding within 5 days, but the quality of the evidence varies, and terlipressin is the only one that has been shown to be effective in controlling bleeding, decreasing transfusion requirements, and reducing 6week mortality in placebo controlled clinical trials. A large headtohead study claiming equal efficacy should be treated with caution, as it used subtherapeutic doses of terlipressin and subopti mal doses of somatostatin [79]. Rifaximin may also be effec tive, but has not been specifically investigated yet in this scenario. Specific haemostatic therapy Emergency endoscopy should be scheduled as soon as possible, within 12 h of admission. Erythromycin (250 mg iv) prior to endoscopy accelerates gastric emptying and improves visibility at endoscopy [55]. After this the previous treatment approach does not stratify ther apy for known risk factors. This approach is now recommended for the approximately 20% of patients who fulfil these criteria and are treated in centres with enough experience. Oesophageal stents have the addi tional advantages of not interfering with nutrition and of being able to be kept in place for up to 1 week, thus main taining haemostasis while the patient is treated (or recov ers) from concomitant complications, thus facing definitive/elective therapy in much better conditions. The stent is placed without the need for endoscopy and is kept in place for up to 7 days. The intravascular cast is eliminated within ~5 days, leaving areas of extensive avascular ulcerations. These treatments should only be performed by very experienced endoscopists, as otherwise they may be associated with severe complications. The latter might be the only nonsurgical option in some cases with total portal vein thrombosis. As outlined with regard to primary prophylaxis, the concept of improv ing outcomes in variceal bleeding is evolving, and nowadays the aim of therapy in this scenario has changed from preventing rebleeding to decreasing the risk of death, mostly by preventing further episodes of decompensation (complications of cirrhosis) that can lead to death. These include, but are not limited to , rebleeding (which itself is not the major cause of death in these patients) but also ascites, spontaneous bacte rial peritonitis, and hepatic encephalopathy. Therefore, these patients should be carefully considered for liver transplantation. Prevention of recurrent variceal haemorrhage should start as soon as the bleeding episode is controlled, which by convention is set after day 5 (with no signs of bleeding for at least 3 days). These patients have a substantial risk of rebleeding, of about 60% at 1 year (mostly in the initial 3 months), and a high mortality (up to 33% at 1 year) if left untreated [82]. Carvedilol is not yet generally recommended in sec ondary prophylaxis owing to concerns about potential renal adverse events due to hypotension (although this is very infrequent with lowdose carvedilol, at 6. In expert centres, repeat cyanoacr ylate glue injections (two or three sessions) are used. Ultrasonographic evaluation of liver surface and transient elastography in clinically doubtful cirrhosis. The burden of liver disease in Europe: a review of available epidemiological data. The venous anatomy of the lower oesophagus in normal subjects and in patients with varices: an image analysis study. Threedimensional view of the vascular structure of the lower esophagus in clinical portal hypertension. Prevalence, classification and natural history of gastric varices: a longterm followup study in 568 portal hypertension patients. Gastric endoscopic features in portal hypertension: final report of a consensus conference, Milan, Italy, September 19, 1992. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and plateletderived growth factor blockade in rats. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Systemic inflammation in decompensated cirrhosis: characterization and role in acuteonchronic liver failure. International Liver Transplant Society practice guidelines: diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension. Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis. Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: a systematic review and metaanalysis. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Acute 40 41 42 43 44 45 46 47 48 49 50 51 hemodynamic response to betablockers and prediction of longterm outcome in primary prophylaxis of variceal bleeding. Prognostic usefulness of hepatic vein catheterization in patients with cirrhosis and esophageal varices. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Prognostic value of hepatic venous pressure gradient for inhospital mortality of patients with severe acute alcoholic hepatitis. A prospective observational study on tolerance and satisfaction to hepatic haemodynamic procedures. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Chronic liver disease: noninvasive subharmonic aided pressure estimation of hepatic venous pressure gradient. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. Utility of endoscopic 53 54 55 56 57 58 59 60 61 62 63 64 65 ultrasound in patients with portal hypertension. Hemodynamic response to pharmacological treatment of portal hypertension and longterm prognosis of cirrhosis. Development of hyperdynamic circulation and response to beta blockers in compensated cirrhosis with portal hypertension. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic nonresponse to propranolol. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebocontrolled trial. Propranolol plus prazosin compared with propranolol plus isosorbide5mononitrate in the treatment of portal hypertension. Simvastatin attenuates liver injury in rodents with biliary cirrhosis submitted to hemorrhage/resuscitation. Effects of simvastatin administration on rodents with lipopolysaccharideinduced liver microvascular dysfunction. Hemodynamic effects of continuous versus bolus infusion of terlipressin for portal hypertension: a randomized comparison. Early liver failure after transjugular intrahepatic portosystemic shunt in patients with cirrhosis with Model for EndStage Liver Disease score of 12 or less: incidence, outcome, and prognostic factors. Lack of difference among terlipressin, somatostatin, and octreotide in the control of acute gastroesophageal variceal hemorrhage. Esophageal balloon tamponade versus esophageal stent in controlling acute refractory variceal bleeding: a multicenter randomized, controlled trial. Drugs plus ligation to prevent rebleeding in cirrhosis: an updated systematic review. Covered transjugular intrahepatic portosystemic shunt versus endoscopic therapy + betablocker for prevention of variceal rebleeding. Prevention of rebleeding from esophageal varices in patients with cirrhosis receiving smalldiameter stents versus hemodynamically controlled medical therapy. Occlusive or nonocclusive ischaemia of the arteriolar peribiliary plexus induces bile duct necrosis and secondary sclerosing cholangitis. Major causes of ischaemic cholangiopathy include early hepatic artery occlusion after liver transplantation and prolonged critical circulatory conditions. In patients with hereditary haemorrhagic telangiectasia, a variety of microscopic or gross fistulae may result in hepatic arteriovenous, portohepatic venous, and/or arterioportal shunting. Heart failure due to right to left shunting is the most frequent and serious complication of hepatic vascular malformations. Hepatic venous outflow obstruction is mainly due to venous thrombosis caused by prothrombotic conditions. Early anticoagulation prevents progression of the acutely developed thrombus and intestinal ischaemia. Permanent occlusion is associated with the formation of a cavernoma and extrahepatic portal hypertension. Idiopathic intrahepatic noncirrhotic portal hypertension is a poorly understood entity, which can be associated with a variety of rare systemic diseases. Obliterative portal venopathy and nodular regenerative hyperplasia are central features. Hypoxic hepatitis results from circulatory failure, with or without cardiac failure, with or without hypoxaemia, with or without sepsis. Although occasionally marked, it is reversible when the circulatory disorder is reversed. The severity of congestive cardiac hepatopathy parallels the severity of the underlying chronic cardiac failure. Hepatic artery occlusion Blood flow from hepatic arteries is mainly directed to the bile ducts, through a continuous arteriolar peribiliary plexus that also interconnects arterial branches. In normal subjects, after a sudden hepatic arterial occlusion, there is immediate opening of anasto- moses between the intrahepatic, diaphragmatic, or parietal arteries [1]. Causes Causal factors are mostly iatrogenic, occurring during liver, bile duct, or pancreatic surgery, or endoarterial or percutaneous radiological procedures. Occlusion of small arteries or the peribiliary plexus (following smallparticle embolization or arterial infusion of toxic agents) induces ischaemic cholangiopathy. After liver transplantation, the occlusion of large arteries in the transplanted liver causes ischaemic cholangiopathy because accessory transcapsular arteries can no longer act as collaterals. Subsequently, transmural necrosis allows bile to spill over into portal tracts or parenchyma, forming bilomas that may undergo bacterial superinfection. Biliary casts or bilomas may be clinically silent or accompanied by pain, fever, and jaundice. Secondary sclerosing cholangitis can also be clinically silent or present with pruritus or bacterial cholangitis. Increased serum bilirubin levels and laboratory features of systemic inflammation are common. Hepatic infarction can be asymptomatic or accompanied by acute right upper quadrant pain. There is a marked, early, but transient increase in aminotransferases, and a moderate, delayed hyperbilirubinaemia. Management Early diagnosis and intervention are crucial in the post transplant setting. Aneurysms of the hepatic artery Hepatic artery aneurysms account for over half of the cases of splanchnic artery aneurysms.

It is detected as a mobile tumour on the right side of the abdomen which descends with the diaphragm on inspiration homemade antibiotics for dogs buy generic tinidazole 1000mg line. It is easily mistaken for other tumours in this area antibiotics penicillin buy cheapest tinidazole and tinidazole, especially a visceroptotic right kidney antibiotic 1p 272 purchase tinidazole online pills. They are one to six in number and run anteroposteriorly bacteria minecraft 164 cheap generic tinidazole uk, being deeper posteriorly infection kidney buy tinidazole on line. These represent diaphragmatic sulci and fissures produced by pressure exerted by diaphragmatic muscle on peripheral structurally weak liver parenchymal zones associated with watershed vascular distribution [12] quinolone antibiotics for uti tinidazole 500 mg on line. This is a horizontal fibrotic furrow or pedicle on the anterior surface of one or both lobes of the liver just below the costal margin [13]. The mechanism is unknown, but it affects elderly women who have worn corsets for many years. It presents as an abdominal mass in front of and below the liver and is isodense with the liver. Interference with the portal supply or biliary drainage of a lobe may cause atrophy. Left lobe atrophy found at postmortem or during scanning is not uncommon and is probably related to reduced blood supply via the left branch of the portal vein. The lobe is decreased in size with thickening of the capsule, fibrosis, and prominent biliary and vascular markings. Loss of left lobe parenchyma in this instance develops by the process of ischaemic extinction due to impaired flow from the affected large portal vein branch. This large vessel extinction process should be distinguished from cirrhosis in which the entire liver is affected by numerous intrahepatic and discrete extinction lesions, which affect small hepatic veins and portal vein branches during the course of inflammation and fibrosis. Hence, in cirrhosis the entire liver surface is diffusely converted to regenerative parenchymal nodules surrounded by fibrosis. Obstruction to the right or left hepatic bile duct by benign stricture or cholangiocarcinoma is now the most common cause of lobar atrophy [14]. This rare lesion may be an incidental finding associated, probably coincidentally, with biliary tract disease and also with other congenital abnormalities. It must be distinguished from lobar atrophy due to cirrhosis or hilar cholangiocarcinoma. Hepatic surgery (partial hepatectomy, liver transplantation) is feasible, but complex. Other conditions associated with displacement of the liver from its location in the right upper quadrant include congenital diaphragmatic hernias, diaphragmatic eventration, and omphalocoele. Anatomical abnormalities of the gallbladder and biliary tract are discussed in Chapter 14. This is soon joined by the cystic duct from the gallbladder to form the common bile duct. The common bile duct runs between the layers of the lesser omentum, lying anterior to the portal vein and to the right of the hepatic artery. Passing behind the first part of the duodenum in a groove on the back of the head of the pancreas, it enters the second part of the duodenum. The duct runs obliquely through the posteromedial wall, usually joining the main pancreatic duct to form the ampulla of Vater (c. Using endoscopic cholangiography, the duct diameter is usually less than 11 mm, although after cholecystectomy it may be more in the absence of obstruction. The duodenal portion of the common bile duct is surrounded by a thickening of both longitudinal and circular muscle fibres derived from the intestine. It always lies above the transverse colon, and is usually next to the duodenal cap overlying, but well anterior to , the right renal shadow. The fundus is the wider end and is directed anteriorly; this is the part palpated when the abdomen is examined. The valves of Heister are spiral folds of mucous membrane in the wall of the cystic duct and neck of the gallbladder. The mucosa is in delicate, closely woven folds; instead of glands there are indentations of mucosa which usually lie superficial to the muscle layer. The gallbladder wall consists of a loose connective tissue lamina propria and muscular layer containing circular, longitudinal, and oblique muscle bundles without definite layers, the muscle being particularly well developed in the neck and fundus. The distensible normal gallbladder fills with bile and bile acids secreted by the liver, concentrates the bile through absorption of water and electrolytes and with meals contracts under the influence of cholecystokinin (acting through preganglionic cholinergic nerves) to empty bile into the duodenum. This branch of the hepatic artery is large, tortuous, and variable in its anatomical relationships. The venous drainage is into the cystic vein and thence into the portal venous system. The arterial blood supply to the supraduodenal bile duct is generally by two main (axial) vessels which run beside the bile duct. These are supplied predominantly by the retroduodenal artery from below, and the right hepatic artery from above, although many other vessels contribute. This pattern of arterial supply would explain why vascular damage results in bile duct stricturing [16]. These drain through the cystic gland at the neck of the gallbladder to glands along the common bile duct, where they anastomose with lymphatics from the head of the pancreas. The gallbladder and bile ducts are liberally supplied with nerves, from both the parasympathetic and the sympathetic system. The upper border of the right lobe is on a level with the 5th rib at a point 2 cm medial to the right midclavicular line (1 cm below the right nipple). The upper border 6 Chapter 1 of the left lobe corresponds to the upper border of the 6th rib at a point in the left midclavicular line (2 cm below the left nipple). The lower border passes obliquely upwards from the 9th right to the 8th left costal cartilage. In the right nipple line it lies between a point just under to 2 cm below the costal margin. It crosses the midline about midway between the base of the xiphoid and the umbilicus and the left lobe extends only 5 cm to the left of the sternum. A line is drawn from the left anterior superior iliac spine through the umbilicus; its intersection with the right costal margin indicates the position of the gallbladder. The lower edge should be determined by palpation just lateral to the right rectus muscle. This avoids mistaking the upper intersection of the rectus sheath for the liver edge. The lower edge may be displaced downwards by a low diaphragm, for instance in emphysema. Common causes of a liver palpable below the umbilicus are malignant deposits, polycystic or Hodgkin disease, amyloidosis, congestive cardiac failure, and gross fatty change. Rapid change in liver size may occur when congestive cardiac failure is corrected, cholestatic jaundice relieved, or when severe diabetes is controlled. The surface can be palpated in the epigastrium and any irregularity or tenderness noted. Pulsation of the liver, usually associated with tricuspid valvular incompetence, is felt by manual palpation with one hand behind the right lower ribs posteriorly and the other anteriorly on the abdominal wall. The upper edge is determined by fairly heavy percussion passing downwards from the nipple line. The lower edge is recognized by very light percussion passing upwards from the umbilicus towards the costal margin. Method I: the gallbladder is found where the outer border of the right rectus abdominis muscle intersects the 9th costal cartilage. The anterior liver span is obtained by measuring the vertical distance between the uppermost and lowermost points of hepatic dullness by percussion in the right midclavicular line. Friction may be palpable and audible, usually due to recent biopsy, tumour, or perihepatitis. The venous hum of portal hypertension is audible between the umbilicus and the xiphisternum. An arterial murmur over the liver may indicate a primary liver cancer or acute alcoholic hepatitis. In a thin person, the swelling can sometimes be seen through the anterior abdominal wall. The swelling is dull to percussion and directly impinges on the parietal peritoneum, so that the colon is rarely in front of it. This is the inability to take a deep breath when the examining fingers are hooked up below the liver edge. The inflamed gallbladder is then driven against the fingers and the pain causes the patient to catch their breath. This, however, is more mobile, can be displaced towards the pelvis and has the resonant colon anteriorly. A plain film of the abdomen, including the diaphragms, may be used to assess liver size and in particular to decide whether a palpable liver is due to actual enlargement or to downward displacement. On moderate inspiration the normal level of the diaphragm, on the right side, is opposite the 11th rib posteriorly and the 6th rib anteriorly. Cords (plates) of liver cells and bloodcontaining sinusoids extend between these two systems. The lobule has foundations in pig, camel, raccoon, and polar bear livers, in which such hexagonal units are surrounded by interlobular connective tissue septa [20]. Histological sections of normal liver show portal tracts containing dyads as frequently as triads, with the portal vein being the most frequently absent element. Within each linear centimetre of liver tissue obtained at biopsy there are usually two interlobular bile ducts, two hepatic arteries and one portal vein per portal tract, with six full portal triads [21]. Traditionally, the unit is based on a central hepatic vein and its surrounding liver cells. These interdigitate, mainly perpendicularly, with terminal hepatic veins of adjacent acini. The circulatory peripheries of acini (adjacent to terminal hepatic veins) (zone 3) suffer most from injury, whether viral, toxic, or anoxic. The regions closer to the axis formed by afferent vessels and bile ducts survive longer and may later form the core from which regeneration will proceed. The contribution of each acinar zone to liver cell regeneration depends on the acinar location of damage [22]. The sinusoids are lined by endothelial cells with small pores (fenestrae) for macromolecule diffusion from Microanatomy of the liver For over a century, many models of liver substructure have been proposed [18]. The most popular of these is the lobule introduced by Kiernan in 1833 as the basic architectural unit, based on pig dissections [19]. The space of Disse between hepatocytes and sinusoidal endothelial cells contains a few collagen fibrils and the hepatic stellate cells, which have also been called fat storing cells, Ito cells, and lipocytes. These cells store vitamin A and when activated in disease become collagensynthesizing myofibroblasts. The hepatic lymphatics are found in the periportal connective tissue and are lined throughout by endothelium. Anatomy and Function 9 the branch of the hepatic arteriole forms a plexus around the bile ducts and supplies the structures in the portal tracts. These are formed by modifications of the contact surfaces of liver cells and are covered by microvilli. The plasma membrane is reinforced by microfilaments forming a supportive cytoskeleton. The canalicular surface is sealed from the rest of the intercellular surface by junctional complexes including tight junctions, gap junctions, and desmosomes. The intralobular canalicular network drains into the canals of Hering lined by low cuboidal epithelium which connect via short bile ductules to the larger terminal bile ducts within the portal tracts. Bile ducts are classified into small (less than 100 m in diameter), medium (about 100 m), and large (more than 100 m) calibre types. From it, equally sized and spaced microvilli project into the lumen of the bile canaliculi. Along the sinusoidal border, irregularly sized and spaced microvilli project into the perisinusoidal tissue space. The microvillous structure indicates active secretion or absorption, mainly of fluid. The nucleus has a double contour with pores allowing interchange with the surrounding cytoplasm. Human liver after puberty contains tetraploid nuclei and, at about age 20, in addition, octoploid nuclei are found.

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