Liver Cirrhosis.pdf

1 LIVER CIRRHOSIS By Prof. Hoda El Aggan Professor of Internal Medicine (Hepato-Biliary Pancreatic Unit) Faculty of Medicine, Alexandria University ILOs At...

1 LIVER CIRRHOSIS By Prof. Hoda El Aggan Professor of Internal Medicine (Hepato-Biliary Pancreatic Unit) Faculty of Medicine, Alexandria University ILOs At the end of this session, the student will be able to: ▪ Know the definition, causes, and morphological classification of cirrhosis. ▪ Understand the pathogenesis of cirrhosis. ▪ Describe the clinical manifestations and complications of cirrhosis. ▪ Describe the diagnosis and prognosis of cirrhosis and the prognostic scoring systems. ▪ Outline the treatment of cirrhosis. ▪ Recognize acute-on-chronic liver failure. ▪ Review cardiopulmonary complications of cirrhosis. Introduction The sinusoidal endothelial cells Normal liver (SECs) form the endothelial lining of sinusoids and are characterized by Hepatocytes fenestrations between cells that allow Space of Dissë the exchange of fluid and nutrients Quiescent between the sinusoids and the HSC SECs hepatocytes. The hepatic stellate cells (HSCs), the Fenestra major fibrogenic cells in the liver, are present in the space of Dissë located Sinusoid between the hepatocytes and the Figure 1: Quiescent hepatic stellate sinusoidal endothelial lining. In the cells (HSCs) in the space of Dissë. normal liver, HSCs are inactive SECs, sinusoidal endothelial cells. (quiescent HSCs) and their function is to store vitamin A and retinoids. (Figure 1). El Aggan H  2 Definition Cirrhosis is defined anatomically as a diffuse process with fibrosis and regenerative nodule formation resulting in disruption of the normal architecture of the liver. It is the end result of the fibrogenesis process that occurs with chronic liver injury. Morphological classification Morphologically, cirrhosis is classified as macronodular, micronodular, or mixed. - Macronodular cirrhosis: Nodules are variable in size and > 3mm in diameter (Figure 2.A). Causes include e.g. hepatitis B and C, alpha-1 antitrypsin deficiency, and primary biliary cholangitis (PBC). - Micronodular cirrhosis: Nodules are uniform and < 3mm in diameter involving every lobule (Figure 2.B). This is due to impaired regenerative capacity of the liver. Causes include e.g. alcoholic, hemochromatosis, hepatic venous outflow obstruction, and chronic biliary obstruction. - Mixed cirrhosis: Features of both micronodular and macronodular cirrhosis are present. Usually, micronodular cirrhosis progresses into macronodular cirrhosis over time. (A) (B) Figure 2: Liver cirrhosis. (A) macronodular cirrhosis and (B) micronodular cirrhosis. Causes Causes of liver cirrhosis are summarized in Table 1. El Aggan H  3 Table 1: Causes of liver cirrhosis Viral hepatitis B, C, and D Alcohol Metabolic disease: Metabolic dysfunction-associated steatohepatitis (MASH) (formerly known as non-alcoholic steatohepatitis (NASH)) Hemochromatosis (iron overload) Wilson disease (copper overload) Alpha1 anti-trypsin deficiency Type IV glycogenosis Galactosemia Tyrosenemia Prolonged cholestasis: Primary biliary cholangitis Primary sclerosing cholangitis Prolonged extrahepatic cholestasis Hepatic venous outflow block: Budd Chiari syndrome Sinusoidal obstruction syndrome (Veno-occlusive disease) Right Heart failure (Cardiac cirrhosis) Constrictive pericarditis Autoimmune hepatitis Toxins and drugs, e.g. methotrexate, amiodarone Syphilis (tertiary) Cryptogenic (When the etiology cannot be determined) Pathogenesis Cirrhosis is the result of hepatic injury that leads to both fibrosis and regenerative nodules throughout the liver. Hepatic fibrosis follows hepatocellular necrosis. In viral hepatitis and hemochromatosis, fibrosis is mainly in the periportal zone “zone 1” while in alcoholism and right heart failure, fibrosis is predominantly in zone 3. Fibrosis (collagen) progresses from a reversible to an irreversible state where acellular permanent septa develop. During liver injury, HSCs become activated, transform into myofibroblasts, and start depositing collagen, which results in fibrosis. Abnormal connective tissue matrix is laid down in the space of Dissë “collagenosis of Dissë space” and along sinusoidal lining, leading to defenestration of the sinusoidal wall “capillarization of the sinusoids” and so impeding metabolic exchange with the liver cells (Figure 3). Cell death result in the secretion of growth factors that act on surviving hepatocytes leading to regenerative nodule formation. El Aggan H  4 Both fibrosis and regenerative nodules Injured liver disturb the normal hepatic architecture and subsequently full cirrhosis Hepatocytes develops. Space of Dissë Portal hypertension (PH) in cirrhosis Collagen Activated HSC develops initially as a consequence of an increased intrahepatic vascular resistance. At a critical level of portal Loss of fenestra SECs pressure elevation, there is opening of pre-existing portosystemic collaterals Sinusoid or shunts (PSS) in order to decompress the portal circulation. However, the Figure 3: Activated hepatic stellate increase in portal pressure is cells. SECs, sinusoidal endothelial aggravated due to an increase in portal cells. blood inflow secondary to splanchnic arteriolar vasodilatation (refer to Portal hypertension). The loss of endothelial cell fenestrations and hepatocyte microvilli associated with this ‘capillarization’ of sinusoids impedes the metabolic exchange between blood and hepatocytes resulting in hepatic dysfunction. Also, diversion of portal blood past functioning liver tissue leads to vascular insufficiency at the center of the regenerative nodules. Clinical presentation Cirrhosis is diagnosed by the characteristic morphological changes of the liver. The clinical features of a cirrhotic liver are shrunken, enlarged or normal size, sharp edge which may be irregular, smooth or nodular surface, firm consistency, and usually not tender. Symptoms and signs of cirrhosis result from major complications including (A) PH, (B) hepatic decompensation (liver failure) and (C) hepatocellular carcinoma (HCC). Prognosis and treatment depend on the magnitude of these complications. A) Manifestations of portal hypertension PH is the earliest and most important consequence of cirrhosis and plays a critical role in the development of several complications of cirrhosis. It develops regardless of the severity of liver disease. Clinically, PH is presented as manifestations of PSS, splenomegaly and ascites (refer to Portal hypertension). PSS may clinically present with upper gastrointestinal (GI) bleeding (hematemesis and melena or melena alone), lower GI bleeding (less commonly), dilated abdominal wall veins, caput medusa and a venous hum. El Aggan H  5 Splenomegaly may clinically present with left hypochondrial pain and hypersplenism. Ascites is due to the accumulation of endogenous vasodilators. PH acts as a localizing factor facilitating the transudation of fluid from intravascular compartment to the peritoneal cavity. B) Manifestations of hepatic decompensation Depending on the absence or presence of liver failure (decompensation), clinical cirrhosis is mainly classified into "compensated" and "decompensated" stages respectively, which have entirely different prognosis. Compensated cirrhosis Compensated cirrhosis is defined by the absence of clinical complications of hepatic decompensation (absence of present or past episode of hepatic decompensation). Patients with compensated cirrhosis are typically asymptomatic and their disease may be detected incidentally by physical exams, laboratory investigations, or imaging. Cirrhotic liver and enlarged spleen are present on examination. Variceal bleeding may occur. The precipitating factors for hepatic decompensation include variceal bleeding, major surgery, bacterial infections, HCC, and superimposed liver damage, such as acute alcoholic hepatitis, drug-induced liver injury, superimposed viral hepatitis (hepatitis A virus, hepatitis E virus), and HBV flares. Decompensated cirrhosis Decompensated cirrhosis is a symptomatic disease state marked by the presence of manifestations of liver failure. The transition from compensated cirrhosis to decompensated cirrhosis (first decompensation) may be insidious, resulting from slowly declining hepatic synthetic function and rising portal pressure or acute with onset of symptoms developing over a matter of hours or days leading to the rapid deterioration in liver function. Patients with decompensated cirrhosis have at least one complication; the most frequent are ascites, HE, coagulopathy with or without jaundice: Ascites is the most frequent first decompensating event in cirrhosis and presents with abdominal distension, full flanks, umbilical hernia, and scrotal edema with or without peripheral edema, and may be associated with pleural effusion (hepatic hydrothorax). El Aggan H  6 Hepatic encephalopathy (HE) manifests with fetor hepaticus, asterixis (flapping tremors), disturbed sleep rhythm, disturbed consciousness, psychiatric changes, behavior changes and motor changes. Coagulopathy with spontaneous (easy) bruising, ecchymosis and bleeding tendency is due to deficient synthesis of clotting factors by the liver. Jaundice alone (in non-cholestatic etiologies) is not an early manifestation of cirrhosis in most patients and it may reflect superimposed liver injury. Endocrine changes including hypogonadism and feminization (small soft testicles, impotence, loss of lipido, infertility), gynecomastia and loss of secondary sexual hair (scant chest/axillary/abdomen hair) are the result of decreased estrogen metabolism and hyperestrogenemia. Women can develop amenorrhea and irregular menstrual bleeding, as well as infertility. Vascular changes with spider angiomas (central arterioles surrounded by multiple smaller vessels that look like a spider present invariably on the upper half of the body), and palmar erythema (mottled redness of the thenar and hypothenar eminences) are due to hyperestrogenemia. White nails may be present. Cardiopulmonary manifestations include hyperdynamic circulatory syndrome, cirrhotic cardiomyopathy, portopulmonary hypertension, and hepatopulmonary syndrome as will be discussed later. Increased risk to infections with bacteremia and endotoxemia is due to bacterial translocation and cirrhosis-associated immune dysfunction. Bacterial translocation is defined as passage of bacteria and their products from the gut to the circulation secondary to intestinal wall hyperpermeability due to PH. Infections include urinary tract infection, pneumonia, tuberculous peritonitis, spontaneous bacterial peritonitis (SBP), and fungal infections. Loss of weight due to abnormal catabolic metabolism and malnutrition is common in cirrhosis. Patients with cirrhosis are in a state of ‘accelerated starvation’ that is an impaired adaptive response to short periods of fasting. Sarcopenia (defined by loss of muscle mass) is associated with greater risk for morbidity and mortality. The mechanism of sarcopenia is multifactorial including alterations in protein turnover, energy disposal, hormonal (increased myostatin, decreased anabolic hormones), metabolic changes (altered lipid and amino acid metabolism), and hyperammonemia, which leads to muscle depletion. Further decompensation Further decompensation in cirrhosis represents a more severe stage of decompensated cirrhosis with worsening of PH and circulatory dysfunction and is associated with an even higher mortality than that associated with first decompensation. El Aggan H  7 Specific events that define further decompensation are development of recurrent variceal bleeding, recurrent HE, refractory ascites, SBP, hepatorenal syndrome-acute kidney injury (HRS-AKI), bacterial infections, and acute-on-chronic liver failure (ACLF). C) Hepatocellular carcinoma HCC is frequent with all forms of cirrhosis except the biliary and cardiac types. HCC may be asymptomatic or presents with right hypochondrial pain and/or a focal hepatic lesion. Malignant liver is enlarged, hard in consistency with sharp irregular edge, and nodular surface. An arterial bruit is heard over the mass. Hemorrhagic ascites may develop (refer to Hepatocellular carcinoma). Other manifestations Other manifestations of cirrhosis include digital clubbing, bilateral parotid enlargement, Duputyren contracture, and pigment gallstones. Relative adrenal insufficiency may relate in part to a reduced synthesis of cholesterol and increased levels of proinflammatory cytokines. Associated specific clinical manifestations of primary liver disease may be present according to the etiology of cirrhosis. Acute-on-chronic liver failure ACLF is a clinical syndrome of acute hepatic decompensation in patients with pre-existing chronic liver disease associated with multiorgan failure and high short-term (28-day) mortality (≥ 15%). ACLF can develop at any stage from compensated cirrhosis to decompensated cirrhosis. The precipitating factors include acute alcoholic injury, bacterial infections, reactivation of hepatitis B, flare of autoimmune hepatitis, superimposed acute hepatitis A, and E infection, GI bleeding, and drug hepatotoxicity. The pathophysiology is thought to involve intense systemic inflammation due to infections, acute liver damage, and probably, intestinal translocation of bacteria or bacterial products. Acute decompensation presents as acute development or worsening of cirrhosis-related complications such as ascites, GI bleeding, overt HE, and/or jaundice as well as bacterial infections in patients. Extrahepatic organ failures include renal, coagulation, respiratory, circulatory, and brain failure. The Chronic Liver Failure (CLIF) Organ Failure (CLIF-OF) score and the CLIF Consortium ACLF (CLIF-C ACLF) score predict short-term mortality in patients with ACLF. The CLIF-C ACLF score was calculated by combining the CLIF-OF score, age, and white blood cell (WBC) count. El Aggan H  8 ACLF is graded according to the number of organ failures and type of organ: - No ACLF: No organ failure or single non-kidney organ failure, creatinine < 1.5 mg/dl, no HE. - ACLF Ia: Single renal failure. - ACLF Ib: Single non-kidney organ failure, creatinine 1.5-1.9 mg/dl and/or HE grade 1-2. - ACLF II: Two organ failures. - ACLF III: Three or more organ failures with a CLIF-C ACLF score ≤ 64. Diagnosis The diagnosis of cirrhosis depends on demonstrating widespread nodules in the liver combined with fibrosis. Imaging Ultrasound (US) is helpful for assessing liver cirrhosis by detecting surface nodularity, dense reflective echoes, enlarged caudate lobe, and regenerating nodules (Figure 4). Splenomegaly and ascites can be detected. US is a screening tool for HCC in cirrhotic patients with or without AFP every 6 months. Computed tomography (CT) can identify liver nodules, fatty change, and a space- Figure 4: Ultrasound scan of occupying lesion e.g. HCC (multiphase liver cirrhosis showing CT). irregular edges (arrow) and a coarse echo pattern. Magnetic resonance imaging (MRI) is useful in evaluating liver nodules and possible malignancy e.g. HCC (multiphase MRI), the level of iron (hemochromatosis) and fat deposition (steatosis) in the liver, and biliary obstruction (magnetic resonance cholangiopancreatography (MRCP)). Liver biopsy Liver biopsy usually guided by US or CT, is the gold standard for the diagnosis of cirrhosis. It may be difficult but gives a clue to the etiology and inflammatory activity. Serial biopsies are valuable in assessing progress. Reticulin and collagen stains are for the demonstration of fibrosis. Special stains can help in establishing the etiology of cirrhosis. Transjugular route is used if there are contraindications, such as ascites or a coagulation defect. El Aggan H  9 However, liver biopsy is invasive and can lead, even if rarely, to severe complications including bleeding, infection, and accidental injury to nearby organs. Noninvasive tests for assessment of liver fibrosis Noninvasive tests are tools for the assessment of liver fibrosis. Blood-based tests are simple non-invasive scores that are widely used to assess the severity of liver fibrosis and can be calculated from routine blood tests: - The aspartate aminotransferase (AST) to platelet ratio index (APRI) (calculated using AST and platelet count). - Fibrosis-4 index (FIB-4) (calculated using age, AST, alanine aminotransferase (ALT), and platelet count). - Advanced fibrosis is predicted at a value of >1.5 for APRI and >3.25 for FIB-4. Liver elastography is a non-invasive method (US-based or MRI-based) that measures liver stiffness and correlates with liver fibrosis. The vibration controlled transient elastography (TE) (commonly known by the brand name FibroScan™) is the most widely validated tool for the prediction of advanced fibrosis and cirrhosis. - TE is an ultrasound-based non-imaging technique (no B-mode ultrasound) in which mechanical (shear) waves generated by a special transducer propagate through the liver. The velocity of these waves is related to liver stiffness. Basically, the stiffer the liver, the faster the wave passes through the liver. The shear wave velocity is converted to a liver stiffness measurement (LSM) in kilopascals (kPa). - LSM >12.5 kPa is highly suggestive for cirrhosis. - However, the results of liver stiffness measurement can overestimate liver fibrosis in case of hepatic inflammation, cholestasis, food ingestion, exercise, or venous congestion. Laboratory findings Liver test profile reflects hepatocellular injury and dysfunction. In decompensated cirrhosis, serum albumin is low as it is synthesized by the liver while prothrombin time (PT) is prolonged due to coagulation factor defects. Serum aminotransferases are usually mildly to moderately elevated with aspartate aminotransferase (AST) greater than alanine aminotransferase (ALT); however, normal levels do not exclude cirrhosis. Serum bilirubin and gamma-glutamyl transpeptidase (GGT) may be elevated in cirrhosis. El Aggan H  10 Immunoglobulins (Ig), especially gamma-globulins, are usually elevated due to impaired clearance by the liver. Complete blood picture may show abnormalities. - Anemia, a frequent finding in cirrhosis, may be (i) normocytic normochromic anemia due to acute GI bleeding, hypersplenism, or bone marrow aplasia due to alcohol or HCV infection, (ii) microcytic hypochromic with chronic occult blood loss from the GI tract or anemia of chronic disease or (iii) macrocytic due to vitamin B12 and folate deficiency. - Erythrocytosis may occur with HCC due to excess thrombopoietin production by tumor cells. - White blood cell count may be low, reflecting hypersplenism or high, suggesting infection. - Thrombocytopenia is secondary to hypersplenism, thrombopoietin deficiency, immune thrombocytopenia, as well as suppression effect on the bone marrow by alcohol or HCV. Renal function, serum electrolytes and serum alpha fetoprotein (AFP) should be monitored. The diagnosis of etiology of cirrhosis can be evaluated by specific tests e.g. - Hepatitis B, C and D viral markers - An increase in transferrin saturation, serum ferritin, serum iron, hepatic iron concentration, and genetic testing in hemochromatosis. - Low serum ceruloplasmin, high 24-hour urine copper excretion, and increased hepatic copper concentration in Wilson disease. - Presence of autoantibodies and elevated serum IgG levels in autoimmune- related cirrhosis. - Alpha 1-antitrypsin level and protease inhibitor phenotype for alpha 1- antitrypsin deficiency. - Anti-mitochondrial antibodies for PBC. - High fasting plasma glucose and gylcated hemoglobin (HbA1c) and/or hyperlipidemia in MASH/NASH. Other tests Endoscopy confirms the presence of varices and detects specific causes of bleeding in the esophagus, stomach, and proximal duodenum. Screening for HCC should be scheduled every 6 months with ultrasound examination (with or without AFP assay). El Aggan H  11 Hepatic venous pressure gradient (HVPG) measurement may establish the presence and cause of PH and response to therapy (refer to Portal hypertension). Prognosis The risk of death in patients with compensated cirrhosis is low (median survival time > 12 years). Patients without varices have a significantly lower mortality than those with varices. The transition from compensated asymptomatic cirrhosis to decompensated cirrhosis occurs at a rate of about 5-7% per year with a drop in median survival to about two years for decompensated cirrhosis. Poor prognosis in cirrhosis is associated with a marked ascites (if refractory), variceal bleeding, advanced age, mean arterial pressure 82 mm Hg or less, high daily alcohol consumption, prolonged prothrombin time, high serum bilirubin and alkaline phosphatase, low albumin values, hyponatremia, infections, severe kidney dysfunction, ventilatory insufficiency, and poor nutrition. Patients with cirrhosis are at risk for the development of HCC, with rates of 3–5% per year for alcohol-associated and viral hepatitis–related cirrhosis. Prognostic scoring systems The Child-Pugh classification and the Model for End‐stage Liver Disease (MELD) score are currently the most utilized scoring systems to assess the severity of liver disease. Child-Pugh classification The Child-Pugh classification depends on 5 parameters: ascites, encephalopathy, serum albumin, bilirubin, and prothrombin time (Table 2) and gives a good short-term prognostic guide. The total score classifies patients into class A (5-6 points); Class B (7-9 points); Class C (10-15 points). One- and two-year survival rates for these classes are 100% and 85% (class A), 80% and 60% (class B), and 45% and 35% (class C). Table 2: Child-Pugh classification. Points scored Variable 1 2 3 Encephalopathy None Stage 1-2 Stage 3-4 Ascites Absent Mild to moderate Severe Bilirubin (mg/dL) 3 Albumin (g/dL) >3.5 2.8-3.5 64. CIRRHOSIS-RELATED CARDIOPULMONARY COMPLICATIONS Hyperdynamic circulatory syndrome The hyperdynamic circulatory syndrome is a well-known clinical condition found in patients with cirrhosis and PH and is characterized by increased cardiac output, hypervolemia (sodium and water retention), rapid heart rate, low arterial blood pressure, increased pulse rate and volume with bounding character, and a systolic murmur. The main cause of the syndrome is systemic vasodilatation as PSS permit endogenous vasodilators to bypass the liver and reach the systemic circulation. The hyperdynamic circulatory syndrome is the pathogenetic basis for the development of several complications of cirrhosis such as ascites, HRS, and hepatopulmonary syndrome. Cirrhotic cardiomyopathy Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction in patients with cirrhosis in the absence of known cardiac disease. CCM is characterized by: - An impaired cardiac response to stress. - Left ventricular diastolic and/or systolic dysfunctions. El Aggan H  16 - A hyperdynamic circulatory state. - Electrophysiologic abnormalities most notably QT prolongation and chronotropic incompetence (the inability to increase the heart rate adequately during exercise to match cardiac output to metabolic demands). Major stresses (pharmacological/surgical or inflammatory) such as transjugular intrahepatic portosystemic shunt (TIPS), LT, sepsis, and fluid overload may precipitate overt cardiac failure. Pathogenesis: The suggested pathogenic mechanisms include defects in the cardiomyocyte β-adrenergic signaling pathway (due to activation of sympathetic nervous system (autonomic dysfunction)), an overproduction of cardiodepressant substances such as nitric oxide, carbon monoxide, and endocannabinoids due to PH, systemic inflammation (due to bacterial translocation), alterations in the lipid composition causing decreased fluidity of the cardiomyocyte plasma membrane, and ion channel defects (defective K+-channel function). Also, shear stress generated by PH exhibiting mechanical forces on myocardial fibers results in an increased stiffness of the myocardial wall because of mild myocardial hypertrophy, fibrosis and subendotelial edema. The inability to increase cardiac output under stress may contribute to sodium and water retention, ascites formation and HRS development. Clinical presentation: CCM is clinically asymptomatic at rest with unremarkable cardiopulmonary disease in most patients with cirrhosis as systemic vasodilation reduces afterload and compensates for abnormal cardiac function. In times of stress, rapid hemodynamic changes with impaired cardiac response will produce symptoms and signs of congestive heart failure. Diagnosis - Echocardiography showing diastolic and/or systolic dysfunction is essential for diagnosis. - As CCM manifests under conditions of stress, a chemical (intravenous dobutamine) or exercise stress echocardiography demonstrating a blunted cardiac response can be useful in confirming this diagnosis. - QT prolongation on electrocardiogram is often the first sign of CCM. - The chest x-ray is typically normal but may show cardiomegaly and pulmonary edema. - Serum markers such as elevated serum brain natriuretic peptide (BNP), or its prohormone N-terminal pro-BNP (NT-proBNP), galactin-3, and cardiac troponin (I or T) are markers of cardiac involvement. El Aggan H  17 Treatment - Diuretics (including aldosterone-antagonists) and NSBBs, in particular carvedilol, may be helpful. - Vasodilators (e.g. angiotensin-converting enzyme inhibitors, angiotensin receptor blockers) should probably be avoided. - TIPS placement is not recommended in patients with CCM as it results in increased preload leading to overt heart failure (i.e. cardiac decompensation). - Liver transplantation frequently improves systolic and diastolic dysfunction and reverses QT prolongation. However, LT is a major risk factor for cardiovascular dysfunction and mortality. Echocardiographic surveillance of transplant candidates with CCM is recommended. Portopulmonary hypertension Portopulmonary hypertension (PoPH) is defined by the presence of pulmonary arterial hypertension (PAH) associated with PH with or without underlying liver disease in the absence of other diseases associated with pulmonary hypertension. The diagnostic criteria for POPH are: - Evidence of PH. - A rise in mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest. - Pulmonary capillary wedge pressure (PCWP) < 15 mmHg. - Pulmonary vascular resistance (PVR) >240 dyne/sec/cm-5). The classification of PoPH is based on the level of mPAP as follows: - Mild PoPH (mPAP of 25– 45 mmHg). The pathogenesis of PoPH is linked to vasoactive mediators produced in the splanchnic circulation and normally metabolized by the liver that reach the pulmonary circulation through PSS. These substances include endothelin- 1A, thromboxane A2, and serotonin that result in increased pulmonary vascular resistance with subsequent injury to pulmonary vessels. High cardiac output in cirrhosis can cause pulmonary artery shear forces that lead to endothelial cell proliferation and increased smooth muscle cells in the vessel wall. Clinical manifestations: Patients with PoPH may remain asymptomatic for a long time. Initial clinical symptoms are commonly subtle and include dyspnea on exertion and fatigue. In case of disease progression, patients may present El Aggan H  18 with chest pain, syncope, orthopnea, dyspnea at rest and signs of pulmonary hypertension and right heart failure. Diagnosis - Transthoracic echocardiography is performed as a screening test for PoPH and other causes of pulmonary hypertension such as left heart disease, chronic lung disease, and venous thromboembolism. A right ventricular systolic pressure (RVSP) ≥45 mmHg is an indication for right heart catheterization. - Right heart catheterization is the only reliable tool for the diagnosis of hemodynamic changes in PoPH. - Electrocardiographic findings such as right atrial enlargement and right ventricular hypertrophy, are considered as additional signs in more advanced cases of PoPH. Treatment - In mild PoPH, no treatment is warranted as LT outcome is not different from POPH-free patients. - Liver transplantation may be curative in PoPH. It is contraindicated in patients with mean PAP > 35 mm Hg. For these patients, treatment of PoPH with pulmonary vasodilators prior to LT should be used with the aim of lowering mean mPAP < 35 mmHg and thus, LT can be pursued. - Eiligible patients with PoPH are given MELD exception points, which prioritize them for transplantation by moving them higher on the waiting list for LT. - Diuretics should be started in case of volume overload and signs of right heart failure, e.g. progressing ascites and peripheral edema, to maintain euvolemia. - Beta-blockers are contraindicated in PoPH as they affect hemodynamics and worsen exercise capacity and calcium channel blockers should be used with caution because they may worsen PH. - TIPS should be avoided in patients with PoPH, as its placement leads to an acute increase in preload that may lead to acute increased right heart pressures and heart failure. Hepatopulmonary syndrome Hepatopulmonary syndrome (HPS) is a defect in oxygenation due to pulmonary vascular dilatation associated with chronic liver disease and/or PH in the absence of detectable primary cardiopulmonary disease. The diagnostic criteria for HPS consist of the following triad: - The presence of liver disease and/or PH. El Aggan H  19 - An elevated age-adjusted alveolar-arterial oxygen gradient (AaPO2) >15 mmHg (or > 20 mmHg when age ≥ 65 years) while breathing room air) with or without hypoxemia (Partial pressure of oxygen (PaO2)