Cardiac Cirrhosis Definition Patients with long-standing right-sided congestive heart failure may develop chronic liver injury

and cardiac cirrhosis. This is an increasingly uncommon, if not rare, cause of chronic liver disease given the advances made in the care of patients with heart failure. Etiology and Pathology In the case of long-term right-sided heart failure, there is an elevated venous pressure transmitted via the inferior vena cava and hepatic veins to the sinusoids of the liver, which ecome dilated and engorged with lood. The liver ecomes enlarged and swollen, and with long-term passive congestion and relative ischemia due to poor circulation, centrilo ular hepatocytes can ecome necrotic, leading to pericentral fi rosis. This fi rotic pattern can e!tend to the periphery of the lo ule outward until a uni"ue pattern of fi rosis causing cirrhosis can occur. Clinical #eatures Patients typically have signs of congestive heart failure and will manifest an enlarged firm liver on physical e!amination. $%P levels are characteristically elevated, and aminotransferases may e normal or slightly increased with $&T usually higher than $%T. It is unli'ely that patients will develop variceal hemorrhage or encephalopathy. Diagnosis The diagnosis is usually made in someone with clear-cut cardiac disease who has an elevated $%P and an enlarged liver. %iver iopsy shows a pattern of fi rosis that can e recogni(ed y an e!perience hepatopathologist. Differentiation from )udd-Chiari syndrome *)C&+ can e made y seeing e!travasation of red lood cells in )C&, ut not in cardiac hepatopathy. ,enoocclusive disease can also affect hepatic outflow and has characteristic features on liver iopsy. ,enoocclusive disease can e seen under the circumstances of conditioning for one marrow transplant with radiation and chemotherapy- it can also e seen with the ingestion of certain her al teas as well as pyrroli(idine al'aloids. This is typically seen in Cari ean countries and rarely in the .nited &tates. Treatment is ased on management of the underlying cardiac disease. /ther Types of Cirrhosis There are several other less common causes of chronic liver disease that can progress to cirrhosis. These include inherited meta olic liver diseases such as hemochromatosis, 0ilson1s disease, 2 antitrypsin * 2 $T+ deficiency, and cystic fi rosis. #or all of these disorders, the manifestations of cirrhosis are similar, with some minor variations, to those seen in other patients with other causes of cirrhosis. Hemochromatosis is an inherited disorder of iron meta olism that results in a progressive increase in hepatic iron deposition which, over time, can lead to a portal- ased fi rosis progressing to cirrhosis, liver failure, and hepatocellular cancer. 0hile the fre"uency of hemochromatosis is relatively common, with genetic suscepti ility occurring in 2 in 345

individuals, the fre"uency of end-stage manifestations due to the disease is relatively low, and fewer than 46 of those patients who are genotypically suscepti le will go on to develop severe liver disease from hemochromatosis. Diagnosis is made with serum iron studies showing an elevated transferrin saturation and an elevated ferritin level, along with a normalities identified y HFE mutation analysis. Treatment is straightforward, with regular therapeutic phle otomy. Wilson's disease is an inherited disorder of copper homeostasis with failure to e!crete e!cess amounts of copper, leading to an accumulation in the liver. This disorder is relatively uncommon, affecting 2 in 75,555 individuals. 0ilson1s disease typically affects adolescents and young adults. Prompt diagnosis efore end-stage manifestations ecome irreversi le can lead to significant clinical improvement. Diagnosis re"uires determination of ceruloplasmin levels, which are low- 38-hour urine copper levels, which are elevated- typical physical e!amination findings, including 9ayser-#leischer corneal rings, and characteristic liver iopsy findings. Treatment consists of copper chelating medications. AT deficiency results from an inherited disorder that causes a normal folding of the $T protein, resulting in failure of secretion of that protein from the liver. It is un'nown

how the retained protein leads to liver disease. Patients with 2$T deficiency at greatest ris' for developing chronic liver disease have the :: genotype, ut only a out 25;356 of such individuals will develop chronic liver disease. Diagnosis is made y determining 2$T levels and genotype. Characteristic P$&-positive, diastase-resistant glo ules are seen on liver iopsy. The only effective treatment is liver transplantation, which is curative. Cystic fibrosis is an uncommon inherited disorder affecting Caucasians of <orthern European descent. $ iliary-type cirrhosis can occur, and some patients derive enefit from the chronic use of .DC$. =ajor Complications of Cirrhosis The clinical course of patients with advanced cirrhosis is often complicated y a num er of important se"uelae that can occur regardless of the underlying cause of the liver disease. These include portal hypertension and its conse"uences of gastroesophageal variceal hemorrhage, splenomegaly, ascites, hepatic encephalopathy, spontaneous acterial peritonitis *&)P+, hepatorenal syndrome, and hepatocellular carcinoma *Ta le 753-3+. Ta le 753-3 Complications of Cirrhosis Portal hypertension >astroesophageal varices Portal hypertensive gastropathy &plenomegaly, hypersplenism $scites Coagulopathy #actor deficiency #i rinolysis Throm ocytopenia )one disease

&pontaneous acterial peritonitis /steopenia ?epatorenal syndrome Type 2 Type 3 ?epatic encephalopathy ?epatopulmonary syndrome Portopulmonary hypertension =alnutrition /steoporosis /steomalacia ?ematologic a normalities $nemia ?emolysis Throm ocytopenia <eutropenia

Portal ?ypertension Portal hypertension is defined as the elevation of the hepatic venous pressure gradient *?,P>+ to @4 mm?g. Portal hypertension is caused y a com ination of two simultaneously occurring hemodynamic processesA *2+ increased intrahepatic resistance to the passage of lood flow through the liver due to cirrhosis and regenerative nodules, and *3+ increased splanchnic lood flow secondary to vasodilatation within the splanchnic vascular ed. Portal hypertension is directly responsi le for the two major complications of cirrhosis, variceal hemorrhage and ascites. Variceal hemorrhage is an immediate life-threatening pro lem with a 35;756 mortality associated with each episode of leeding. The portal venous system normally drains lood from the stomach, intestines, spleen, pancreas, and gall ladder, and the portal vein is formed y the confluence of the superior mesenteric and splenic veins. Deo!ygenated lood from the small owel drains into the superior mesenteric vein along with lood from the head of the pancreas, the ascending colon, and part of the transverse colon. Conversely, the splenic vein drains the spleen and the pancreas and is joined y the inferior mesenteric vein, which rings lood from the transverse and descending colon as well as from the superior two-thirds of the rectum. Thus, the portal vein normally receives lood from almost the entire >I tract. The causes of portal hypertension are usually su categori(ed as prehepatic, intrahepatic, and posthepatic *Ta le 753-7+. Prehepatic causes of portal hypertension are those affecting the portal venous system efore it enters the liver- they include portal vein throm osis and splenic vein throm osis. Posthepatic causes encompass those affecting the hepatic veins and venous drainage to the heart- they include )C&, venoocclusive disease, and chronic rightsided cardiac congestion. Intrahepatic causes account for over B46 of cases of portal hypertension and are represented y the major forms of cirrhosis. Intrahepatic causes of portal hypertension can e further su divided into presinusoidal, sinusoidal, and postsinusoidal causes. Postsinusoidal causes include venoocclusive disease, while presinusoidal causes include congenital hepatic fi rosis and schistosomiasis. &inusoidal causes are related to cirrhosis from various causes. Ta le 753-7 Classification of Portal ?ypertension

Prehepatic Portal vein throm osis &plenic vein throm osis =assive splenomegaly *)anti1s syndrome+ ?epatic Presinusoidal &chistosomiasis Congenital hepatic fi rosis &inusoidal CirrhosisCmany causes $lcoholic hepatitis Postsinusoidal ?epatic sinusoidal o struction *venoocclusive syndrome+ Posthepatic )udd-Chiari syndrome Inferior vena caval we s Cardiac causes Destrictive cardiomyopathy Constrictive pericarditis &evere congestive heart failure

Cirrhosis is the most common cause of portal hypertension in the .nited &tates, and clinically significant portal hypertension is present in @E56 of patients with cirrhosis. Portal vein o struction may e idiopathic or can occur in association with cirrhosis or with infection, pancreatitis, or a dominal trauma. Coagulation disorders that can lead to the development of portal vein throm osis include polycythemia vera- essential throm ocytosis- deficiencies in protein C, protein &, antithrom in 7, and factor , %eiden- and a normalities in the gene regulating prothrom in production. &ome patients may have a su clinical myeloproliferative disorder. Clinical #eatures The three primary complications of portal hypertension are gastroesophageal varices with hemorrhage, ascites, and hypersplenism. Thus, patients may present with upper >I leeding, which on endoscopy is found to e due to esophageal or gastric varices, with the development of ascites along with peripheral edema, or with an enlarged spleen with associated reduction in platelets and white lood cells on routine la oratory testing. Esophageal ,arices /ver the last decade, it has ecome common practice to screen 'nown cirrhotics with

endoscopy to loo' for esophageal varices. &uch screening studies have shown that appro!imately one-third of patients with histologically confirmed cirrhosis have varices. $ppro!imately 4;246 of cirrhotics per year develop varices, and it is estimated that the majority of patients with cirrhosis will develop varices over their lifetime. #urthermore, it is anticipated that roughly one-third of patients with varices will develop leeding. &everal factors predict the ris' of leeding, including the severity of cirrhosis *Child1s class+- the height of wedged-hepatic vein pressure- the si(e of the vari!- the location of the vari!- and certain endoscopic stigmata, including red wale signs, hematocystic spots, diffuse erythema, luish color, cherry-red spots, or white-nipple spots. Patients with tense ascites are also at increased ris' for leeding from varices. Diagnosis In patients with cirrhosis who are eing followed chronically, the development of portal hypertension is usually revealed y the presence of throm ocytopenia- the appearance of an enlarged spleen- or the development of ascites, encephalopathy andFor esophageal varices with or without leeding. In previously undiagnosed patients, any of these features should prompt further evaluation to determine the presence of portal hypertension and liver disease. ,arices should e identified y endoscopy. $ dominal imaging, either y CT or =DI, can e helpful in demonstrating a nodular liver and in finding changes of portal hypertension with intraa dominal collateral circulation. If necessary, interventional radiologic procedures can e performed to determine wedged and free hepatic vein pressures that will allow for the calculation of a wedged-to-free gradient, which is e"uivalent to the portal pressure. The average normal wedged-to-free gradient is 4 mm?g, and patients with a gradient @23 mm?g are at ris' for variceal hemorrhage. ,ariceal ?emorrhageA Treatment Treatment for variceal hemorrhage as a complication of portal hypertension is divided into two main categoriesA *2+ primary prophyla!is and *3+ prevention of re- leeding once there has een an initial variceal hemorrhage. Primary prophyla!is re"uires routine screening y endoscopy of all patients with cirrhosis. /nce varices that are at increased ris' for leeding are identified, then primary prophyla!is can e achieved either through nonselective eta loc'ade or y variceal and ligation. <umerous place o-controlled clinical trials of either propranolol or nadolol have een reported in the literature. The most rigorous studies were those that only included patients with significantly enlarged varices or with hepatic vein pressure gradients @23 mm?g. Patients treated with eta loc'ers have a lower ris' of variceal hemorrhage than those treated with place o over 2 and 3 years of follow-up. There is also a decrease in mortality related to variceal hemorrhage. .nfortunately, overall survival was improved in only one study. #urther studies have demonstrated that the degree of reduction of portal pressure is a significant feature to determine success of therapy. Therefore, it is has een suggested that repeat measurements of hepatic vein pressure gradients may e used to guide pharmacologic therapy- however, this may e cost prohi itive. &everal studies have evaluated variceal and ligation and variceal sclerotherapy as methods for providing primary prophyla!is. Endoscopic variceal ligation *E,%+ has achieved a level of success and comfort with most gastroenterologists who see patients with these complications of portal hypertension. Thus, in patients with cirrhosis who are screened for portal hypertension and are found to have large

varices, it is recommended that they receive either eta loc'ade or primary prophyla!is with E,%. The approach to patients once they have had a variceal leed is first to treat the acute leed, which can e life-threatening, and then to prevent further leeding. Prevention of further leeding is usually accomplished with repeated variceal and ligation until varices are o literated. Treatment of acute leeding re"uires oth fluid and lood product replacement as well as prevention of su se"uent leeding with E,%. The medical management of acute variceal hemorrhage includes the use of vasoconstricting agents, usually somatostatin or /ctreotide. ,asopressin was used in the past ut is no longer commonly used. )alloon tamponade *&engsta'en-)la'emore tu e or =innesota tu e+ can e used in patients who cannot get endoscopic therapy immediately or who need sta ili(ation prior to endoscopic therapy. Control of leeding can e achieved in the vast majority of cases- however, leeding recurs in the majority of patients if definitive endoscopic therapy has not een instituted. /ctreotide, a direct splanchnic vasoconstrictor, is given at dosages of 45;255 gFh y continuous infusion. Endoscopic intervention is employed as first-line treatment to control leeding acutely. &ome endoscopists will use variceal injection therapy *sclerotherapy+ as initial therapy, particularly when leeding is vigorous. ,ariceal and ligation is used to control acute leeding in over B56 of cases and should e repeated until o literation of all varices is accomplished. 0hen esophageal varices e!tend into the pro!imal stomach, and ligation is less successful. In these situations, when leeding continues from gastric varices, consideration for transjugular intrahepatic portosystemic shunt *TIP&+ should e made. This techni"ue creates a portosystemic shunt y a percutaneous approach using an e!panda le metal stent, which is advanced under angiographic guidance to the hepatic veins and then through the su stance of the liver to create a direct portocaval shunt. This offers an alternative to surgery for acute decompression of portal hypertension. Encephalopathy can occur in as many as 356 of patients after TIP& and is particularly pro lematic in elderly patients and in those patients with pree!isting encephalopathy. TIP& should e reserved for those individuals who fail endoscopic or medical management or who are poor surgical ris's. TIP& can sometimes e used as a ridge to transplantation. &urgical esophageal transsection is a procedure that is rarely used and generally is associated with a poor outcome. Prevention of Decurrent )leeding *#ig. 753-2+ /nce patients have had an acute leed and have een managed successfully, attention should e paid to preventing recurrent leeding. This usually re"uires repeated variceal and ligation until varices are o literated. )eta loc'ade may e of adjunctive enefit in patients who are having recurrent variceal and ligation- however, once varices have een o literated, the need for eta loc'ade is lessened. Despite successful variceal o literation, many patients will still have portal hypertensive gastropathy from which leeding can occur. <onselective eta loc'ade may e helpful to prevent further leeding from portal hypertensive gastropathy once varices have een o literated. #igure 753-2

Management of recurrent variceal hemorrhage. This algorithm descri es an approach to management of patients who have recurrent leeding from esophageal varices. Initial therapy is generally with endoscopic therapy often supplemented y pharmacologic therapy. 0ith control of leeding, a decision needs to e made as to whether patients should go on to a surgical shunt or TIP& *if they are Child1s class $+ and e considered for transplant, or if they should have TIP& and e considered for transplant *if they are Child1s class ) or C+. TIP&, transjugular intrahepatic portosystemic shunt. Portosystemic shunt surgery is less commonly performed with the advent of TIP&nonetheless, this procedure should e considered for patients with good hepatic synthetic function who could enefit y having portal decompressive surgery. &plenomegaly and ?ypersplenism Congestive splenomegaly is common in patients with portal hypertension. Clinical features include the presence of an enlarged spleen on physical e!amination and the development of throm ocytopenia and leu'openia in patients who have cirrhosis. &ome patients will have fairly significant left-sided and left upper "uadrant a dominal pain related to an enlarged and engorged spleen. &plenomegaly itself usually re"uires no specific treatment, although splenectomy can e successfully performed under very special circumstances. ?ypersplenism with the development of throm ocytopenia is a common feature of patients with cirrhosis and is usually the first indication of portal hypertension. $scites Definition $scites is the accumulation of fluid within the peritoneal cavity. /verwhelmingly, the most common cause of ascites is portal hypertension related to cirrhosis- however, clinicians should remem er that malignant or infectious causes of ascites can e present as well, and careful differentiation of these other causes are o viously important for patient care. Pathogenesis The presence of portal hypertension contri utes to the development of ascites in patients who have cirrhosis *#ig. 753-3+. There is an increase in intrahepatic resistance, causing increased portal pressure, ut there is also vasodilatation of the splanchnic arterial system, which in turn results in an increase in portal venous inflow. )oth of these a normalities result in increased production of splanchnic lymph. ,asodilating factors such as nitric o!ide are responsi le for the vasodilatory effect. These hemodynamic changes result in sodium retention y causing activation of the renin-angiotensin-aldosterone system with the development of hyperaldosteronism. The renal effects of increased aldosterone leading to sodium retention also contri ute to the development of ascites. &odium retention causes fluid accumulation and e!pansion of the e!tracellular fluid volume, which results in the formation of peripheral edema and ascites. &odium retention is the conse"uence of a homeostatic response caused y underfilling of the arterial circulation secondary to arterial vasodilatation in the splanchnic vascular ed. )ecause the retained fluid is constantly lea'ing out of the intravascular

compartment into the peritoneal cavity, the sensation of vascular filling is not achieved, and the process continues. ?ypoal uminemia and reduced plasma oncotic pressure also contri ute to the loss of fluid from the vascular compartment into the peritoneal cavity. ?ypoal uminemia is due to decreased synthetic function in a cirrhotic liver. #igure 753-3

Development of ascites in cirrhosis. This flow diagram illustrates the importance of portal hypertension with splanchnic vasodilatation in the development of ascites. G$ntinatriuretic factors include the renin-angiotensin-aldosterone system and the sympathetic nervous system. Clinical #eatures Patients typically note an increase in a dominal girth that is often accompanied y the development of peripheral edema. The development of ascites is often insidious, and it is surprising that some patients wait so long and ecome so distended efore see'ing medical attention. Patients usually have at least 2;3 % of fluid in the a domen efore they are aware that there is an increase. If ascitic fluid is massive, respiratory function can e compromised, and patients will complain of shortness of reath. ?epatic hydrothora! may also occur in this setting, contri uting to respiratory symptoms. Patients with massive ascites are often malnourished and have muscle wasting and e!cessive fatigue and wea'ness. Diagnosis Diagnosis of ascites is y physical e!amination and is often aided y a dominal imaging. Patients will have ulging flan's, may have a fluid wave, or may have the presence of shifting dullness. This is determined y ta'ing patients from a supine position to lying on either their left or right side and noting the movement of the dullness to percussion. &u tle amounts of ascites can e detected y ultrasound or CT scanning. ?epatic hydrothora! is more common on the right side and implicates a rent in the diaphragm with free flow of ascitic fluid into the thoracic cavity. 0hen patients present with ascites for the first time, it is recommended that a diagnostic paracentesis e performed to characteri(e the fluid. This should include the determination of total protein and al umin content, lood cell counts with differential, and cultures. In the appropriate setting, amylase may e measured and cytology performed. In patients with cirrhosis, the protein concentration of the ascitic fluid is "uite low, with the majority of patients having an ascitic fluid protein concentration H2 gFd%. The development of the serum ascites-to-al umin gradient *&$$>+ has replaced the description of e!udative or transudative fluid. 0hen the gradient etween the serum al umin level and the ascitic fluid al umin level is @2.2 gFd%, then the cause of the ascites is most li'ely due to portal hypertension- this is most often in the setting of cirrhosis. 0hen the gradient is H2.2 gFd%, infectious or malignant causes of ascites should e considered. 0hen levels of ascitic fluid proteins are very low, patients are at increased ris' for developing &)P. $ high level of red lood cells in the ascitic fluid signifies a traumatic tap, or perhaps a hepatocellular cancer, or a ruptured omental vari!.

0hen the a solute level of polymorphonuclear leu'ocytes is @345 mm7, then the "uestion of ascitic fluid infection should e strongly considered. $scitic fluid cultures should e o tained using edside inoculation of culture media. $scitesA Treatment Patients with small amounts of ascites can usually e managed with dietary sodium restriction alone. =ost average diets in the .nited &tates contain E to I g of sodium per day and if patients eat at restaurants or fast food outlets, the amount of sodium in their diet can e!ceed this amount. Thus, it is often e!tremely difficult to get patients to change their dietary ha its to ingest H 3 g of sodium per day, which is the amount that is recommended. Patients are fre"uently surprised to reali(e how much sodium is in the standard .& diet and thus it is important to ma'e educational pamphlets availa le to the patient. /ften, a simple recommendation is to eat fresh or fro(en foods, avoiding canned or processed foods, which are usually preserved with sodium. 0hen a moderate amount of ascites is present, diuretic therapy is usually necessary. Traditionally, spironolactone at 255;355 mgFd as a single dose is started, and furosemide may e added at 85;I5 mgFd, particularly in patients who have peripheral edema. In patients who have never received diuretics efore, the failure of the a ove-mentioned dosages suggests that they are not eing compliant with a low-sodium diet. If compliance is confirmed and ascitic fluid is not eing mo ili(ed, spironolactone can e increased to 855;E55 mgFd and furosemide increased to 235;2E5 mgFd. If ascites is still present with these dosages of diuretics in patients who are compliant with a low-sodium diet, then they are defined as having refractory ascites, and alternative treatment modalities including repeated large-volume paracentesis, or a TIP& procedure should e considered *#ig. 753-7+. Decent studies have shown that TIP&, while managing the ascites, does not improve survival in these patients. .nfortunately, TIP& is often associated with an increased fre"uency of hepatic encephalopathy and must e considered carefully on a case- y-case asis. The prognosis for patients with cirrhosis with ascites is poor, and some studies have shown that H456 of patients survive 3 years after the onset of ascites. Thus, there should e consideration for liver transplantation in patients with the onset of ascites. #igure 753-7

Treatment of refractory ascites. In patients who develop a(otemia in the course of receiving diuretics in the management of their ascites, some will re"uire repeated largevolume paracentesis *%,P+, some may e considered for transjugular intrahepatic portosystemic shunt *TIP&+, and some would e good candidates for liver transplantation. These decisions are all individuali(ed.