Liver transplant (LT) is a surgically challenging procedure and offers a great physiological challenge to cardiopulmonary and renal systems. Liver disease affects all the organ system naming cardiovascular, pulmonary, and renal as well as coagulation and electrolytes. Reflecting the complexity of surgery in recipients and effect of advance liver disease on cardiopulmonary system a careful and targeted preoperative evaluation of recipient is required. However with improving surgical and anesthesia techniques and better understanding of postoperative pathophysiology,  it transcended from very high risk procedure to more routinely performed procedure and currently more sicker and old aged patients are being offered LT, making assessment more complicated.
Aim of pre operative evaluation of a patient for LT

• Rule-out any  major co-morbid conditions, which are likely to preclude successful LT
• Prognostication

General preoperative evaluation includes history, ASA classification, detailed airway assessment, physical examination and nutritional assessment. Systemic evaluation is discussed in proceeding text.
Cardiac evaluation
The purpose of cardiac evaluation pre-LT is to assess perioperative risk and to exclude any concomitant cardiopulmonary disorders that would preclude a good long-term outcome.
Active cardiac conditions- unstable coronary syndromes (eg, unstable angina, severe angina, or recent MI), decompensated heart failure, significant arrhythmias, and severe valvular disease require delay or cancellation of surgery. A number of chronic cardiac conditions also merit consideration   and   at   times   may   require further assessment before surgery. These include chronic limiting angina, an MI that is <30 days old but without symptoms of unstable angina, a  prior history of CABG or PCI, compensated heart failure,  moderate valvular disease or prior valve surgery, or stable arrhythmias.
Cardiac condition commonly present in liver disease patients are coronary artery disease, cirrhotic cardiomyopathy, left ventricular outflow tract obstruction, pericardial effusion, prolonged QTc interval.

Cirrhotic cardiomyopathy (CC)
CC appears to be a complex condition that is characterized by a diminished contractile responsiveness to stress, impaired diastolic relaxation, and electrophysiological abnormalities (QT-interval prolongation, electrical and mechanical dyssynchrony and chronotropic incompetence), all in the absence of known cardiac disease. The clinical impact of CC may not manifest due to low systemic vascular resistance but these patients are at the risk acute decompensated heart failure once normal vascular tone is restored post-operatively. So transthoracic echocardiography (TTE) should be used to assess cardiac output, increased left ventricular wall thickness, cardiac chamber enlargement, and significantly impaired systolic and diastolic response to stress, and right ventricular function and enlargement.
Left ventricular hypertrophy and hyperdynamic systolic function in ESLD may result in hemodynamically significant left ventricular outflow tract obstruction (LVOTO). Assessment for LVOTO by TTE is an important component of the pre-operative assessment of LT candidates with left ventricular hypertrophy. Reported incidence of inducible LVOTO on pre-operative DSE is >40% of patients. An outflow gradient of >36 mm Hg found to be significantly associated with intraoperative hypotension.
Prolonged QTc (>440 ms) interval commonly present in ESLD patients and is associated with the risk of ventricular arrhythmias. A prolonged QTc is not a contraindication to LT, but should prompt a search for reversible causes, such as electrolyte disturbance (e.g., hypokalemia or hypomagnesemia) or the use of QT interval-prolonging drugs.
Pericardial effusion should also be assessed with TTE

Coronary Artery Disease (CAD)
The hemodynamic state typical of advanced liver disease results in a low prevalence of systemic hypertension and impaired hepatic production of lipids may reduce serum cholesterol levels. CAD is at least as frequent in LT candidates as in the general population and is influenced by typical cardiovascular risk factors

Current recommendations is that noninvasive stress testing may be considered in liver transplantation candidates with no active cardiac conditions on the basis of the presence of multiple CAD risk factors regardless of functional status. Relevant risk factors among transplantation candidates include diabetes mellitus, prior cardiovascular disease, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia. The specific number of risk factors that should be used to prompt testing is 3 or more
Liver transplantation candidates who have an LVEF less than 50%, evidence of ischemic left ventricular dilation, exercise-induced hypotension, angina, or demonstrable ischemia in the distribution of multiple coronary arteries should be referred to a cardiologist for evaluation and long-term management according to ACC/AHA guidelines for the general population.

Pulmonary issues

• Pleural effusions (hepatic hydrothorax)
• Dilatation  of  the  pulmonary  vasculature  with  shunting  and  hypoxemia  (hepatopulmonary syndrome)
• Portopulmonary hypertension
• Elevation in pulmonary pressures due to the high cardiac output usually seen in liver disease (flow phenomenon).

Portopulmonary Hypertension
It is elevated  pulmonary  artery  pressure  due  to  increased  resistance  to  blood  flow  in pulmonary circulation in patients  with  portal hypertension. Hemodynamically defined [on right heart catheterization (RHC)] by:
• Elevated mean pulmonary artery pressure (> 25 mm Hg at rest, > 30 mm Hg with exercise)
• Increased pulmonary vascular resistance (> 240 dynes.s.cm–5)
• Normal pulmonary artery occlusion pressure (< 15 mm Hg) 
Approximately 20% of patients with cirrhosis have a moderate increase in pulmonary pressures that is evident at the time of echocardiography; however, a few of these are diagnosed with PoPH. Reason  for is that there are two other more common cause for elevated pulmonary artery pressure which are increased cardiac output and increased left-sided filling pressures (flow phenomenon). It   is very important to   distinguish   these   patients   from true PoPH because they have a significantly   better   prognosis than true PoPH and require a different therapeutic approach. For this transpulmonary gradient (mean pulmonary artery pressure - pulmonary artery occlusion pressure: normal < 12 mmHg) should be calculated which is normal or low in case of flow phenomenon. PoPH classified on the basis of mPAP as mild (25-34 mmHg), moderate 35–44 (mmHg) and severe (>45mmHg).
Among patients with chronic liver disease, the prevalence of PoPH is estimated to be 2%, increasing to 4% to 6% among individuals undergoing LT evaluation.
Screening - Right heart catheterization is gold standard for diagnosis of PoPH. In order to appropriately select patients for this invasive and costly procedure, transthoracic echocardiography (TTE) is the most efficient screening tool. TTE noninvasively estimates the systolic pulmonary artery pressure (sPAP), using the peak tricuspid regurgitant (TR) jet velocity and an estimate of central venous pressure. In the absence of pulmonic stenosis or RV outflow tract obstruction, the RV systolic pressure (RVSP) is considered to be equivalent to the sPAP. Current cutoff for RHC is RVSP >45 mmHg along with TTE finding of the presence of: right atrial enlargement, RV enlargement (defined as RV end diastolic diameter >3.3 cm), or reduced   RV systolic function.Other causes of pulmonary hypertension need to be excluded, including left heart failure, recurrent  pulmonary emboli, and sleep apnea.
Milder degrees of POPH do not adversely affect outcome of LT, but mortality rate climbs with more pronounced degrees In a report from the Mayo Clinic mortality was 50% with MPAP >35 mmHg and 100% with MPAP >50 mmHg. However, if MPAP can be reduced by vasodilator therapy to less than 35 mmHg and PVR <400 dynes.s.cm-5 LT is possible, with acceptable short-term outcomes.
Hepatopulmonary syndrome
This syndrome is characterized by the triad of chronic liver disease, arterial hypoxemia and intrapulmonary vascular dilations. Its reported prevalence is 10-20% of LT candidates
Screening of LT candidates by pulse oximetry is indicated to detect HPS patients with a PaO2 <70 mmHg, using a threshold   value   of   SPO2   <96%   at   sea   level   to   trigger complete evaluation.
Diagnostic Criteria for the Hepatopulmonary Syndrome

Dyspnea is non-specific symptom of pulmonary issues in cirrhotics. Presence of spider nevi, digital clubbing, cyanosis, and severe hypoxemia (partial pressure of oxygen, <60 mm Hg) and orthodeoxia strongly suggests hepatopulmonary syndrome. If the partial pressure of oxygen in arterial blood decreases by 5% or more or   by 4 mm Hg or more when the patient moves from a supine to an upright position it is called orthodeoxia.
Diagnosis is confirmed by demonstrating intrapulmonary vascular dilation by either contrast echocardiography or by radiolabeled albumin macro-aggregate scanning. During TTE,   intravenous injection of agitated saline (in order to produce microbubbles) is used to visualize any intrapulmonary shunt, which is defined by  the appearance of microbubbles in the left  heart  4 to 6 beats after the first appearance in the right heart.  Contrast-enhanced echocardiography seems more appropriate than radio-labeled albumin macro-aggregate scanning because it can differentiate between pulmonary and intra-cardiac shunts however the later exactly quantify the intrapulmonary shunting.
Historically prognosis of LT worsens with greater hypoxemia but according to recent literature LT can be safely performed in patients with severe HPS. Severe hypoxemia is not a contraindication for LT in HPS however early transplant is recommended. Current Organ Procurement Transplant  Network/UNOS policy assigns a MELD exception score of 22 for patients with evidence of portal hypertension, intrapulmonary shunting, and a room air PaO2 <60  mmHg, with a 10% mortality equivalent increase in points every 3 months if the PaO2 remains <60 mmHg. Hypoxemia gets corrected within 6 months in most of the patients post transplant.
Hepatic hydrothorax
Hepatic hydrothorax is another manifestation of advanced liver disease with a reported prevalence of 10%. It is defined as development of pleural effusion in cirrhotic patients in the absence of cardiac, pulmonary, or pleural diseases.
Dyspnea, coughing, and chest pain are of the common but nonspecific. It is mostly right sided and transudative in character. The use of thoracentesis is advised to confirm the diagnosis and exclude other possible causes such as infection and malignancy; and to relieve symptoms. Computed tomography is a useful tool in excluding other lesions of the lungs and pleura.
Renal Dysfunction
Renal dysfunction in a patient with cirrhosis has a dramatic effect on prognosis, with a substantial increase in the risk of mortality. The common cause of acute renal dysfunction (ARF) in hospitalized patients with cirrhosis is pre-renal ARF (45%), intra-renal ARF (32%) including acute tubular necrosis (ATN) and glomerulonephritis, hepatorenal syndrome (HRS) (23%) and post-renal ARF (<1%).
Definitions
Recently, a working group composed of representatives from the International Ascites Club and the Acute Dialysis Quality Initiative has proposed the following definitions of renal dysfunction complicating liver disease: acute kidney injury that includes all causes of acute deterioration of renal function with an increase in serum creatinine of >50% from baseline, or a rise in serum creatinine of   >0.3 mg/dL in <48 hours. Chronic renal disease is defined as an estimated glomerular filtration rate (GFR) of <60 mL/min calculated using the Modification of Diet in Renal Disease 6 formula. Acute-on chronic renal dysfunction was proposed to be a combination of these 2 definitions.
 New diagnostic criteria for HRS

• Cirrhosis with ascites
• Serum creatinine >1.5 mg/dl
• No sustained improvement in serum creatinine <1.5 mg/dl after at least 2 days of diuretic withdrawal and plasma volume expansion with albumin. Recommended albumin dose is 1gm/kg body weight per day to a maximum of 100gm/day
• Absence of shock
• No current or recent treatment with nephrotoxic drugs
• Absence of renal parenchymal disease as indicated by proteinuria >500 mg/day, microhematuria (>50 RBCs/ high power field) and/ or abnormal renal ultrasonography

Following specific questions should be answered during preoperative evaluation

• Is GFR normal
• Whether patient has acute or chronic renal dysfunction
• Is acute renal dysfunction is due to prerenal causes ( diuretic withdrawal,infection, lactulose, gastrointestinal bleed),
• Is renal dysfunction is due to parenchymal disease or obstruction
• Is this Hepatorenal syndrome
• What are the metabolic disturbances
• Is dialysis required
• Is simultaneous liver kidney transplant is appropriate.

Evaluation of renal dysfunction in patients with decompensated cirrhosis should include an accurate calculation of the true glomerular filtration rate (GFR) and determination of the precise etiology as it impacts prognosis both with and without LT. It is reasonable to start the assessment with SCr (it should be kept in mind that SCr tends to overestimates the GFR in patients with cirrhosis), a quantitative assessment of urine protein, and renal ultrasound (US). If there is a change from the baseline or a strong suspicion that the SCr value represents a chronically low GFR, a single cystatin C measurement can be obtained or GFR can be assessed with an exogenous marker ( for knowing true GFR) . Any acute rise in SCr should be further evaluated in all patients. For ongoing monitoring of renal function SCr seems to be appropriate. In patients with cirrhosis and renal dysfunction, it is imperative to rule out hypovolemia as the etiology before further expensive and potentially harmful evaluations. Renal ultrasound is not only helpful for ruling out obstructions, but it may also indicate the presence of a chronic process such as cortical thinning or small kidneys. Urinalysis is important in all patients with renal dysfunction. Proteinuria greater than 500 mg/24 hours and abnormal urine sediment are both suggestive of renal parenchymal disease. If renal parenchymal disease is suspected, kidney biopsy may be helpful in determining not only the etiology of dysfunction but also the chronicity. Furthermore, kidney biopsy may be helpful in determining whether or not a liver transplant candidate would be better served by a simultaneous liver-kidney (SLK) transplant.The indication for SLK is following- (1) end stage renal disease (acute HRS etiology excluded) with cirrhosis; (2) liver failure with chronic kidney disease (CKD) and GFR <30 mL/min, (3) acute kidney injury or HRS with creatinine >2.0 mg/dL and dialysis for >8 weeks; or (4) liver failure with CKD and renal biopsy demonstrating >30% glomerulosclerosis or >30% fibrosis.

Obesity
Obesity is on rise in general population as well as liver transplant candidates and has significant effect on outcome of LT. Morbidly obese (BMI, 40.1-50 kg/m2) recipients has significantly higher incidence of primary graft nonfunction, and immediate, 1-year, and 2-year mortality. So morbid obesity is a relative contraindication for LT.
Hyponatremia
Hyponatraemia is commonly associated with portal hypertension and ascites as a result of water retention. A serum sodium <125 mmol/litre should be carefully corrected preoperatively over days or weeks to reduce the risk of pulmonary oedema and central pontine myelinolysis associated with acute perioperative sodium shifts. This is achieved through fluid restriction and use of the aldosterone antagonist, spironolactone.

Infectious disease
Due to hepatocellular dysfunction, LT candidates are at increased risk of a variety of infections, including spontaneous bacterial peritonitis, aspiration pneumonia, urinary tract, and catheter-associated bloodstream infections. All active infections should be treated before proceeding for LT.
Coagulation
Better understanding of the pathophysiology of the coalguopathy in patients with liver disease and routine availability of Point of Care monitoring devices have revolutionized the management of these patients. With multiple retrospective analysis concluding that prophylactic administration of blood products does not prevent bleeding episodes in these patients and worsens post operative outcomes. Management of coagulopathy in these patients should be guided by POC devices and preoperative correction of coagulopathy should only be done in presence of fibrinolysis and active bleeding.  

Focused preoperative assessment and management of LT recipient can convert LT from a morbid procedure to a smooth and routine procedure both for the patient and the  anesthesiologist.