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Clinical Aspects of Hepatic Problems

Created: 4/2/2005


Advanced liver disease is a classic example of multisystem failure resulting from a single organ disease. Historically, even minor surgery on cirrhotic patients resulted in high mortality. Liver transplantation has dramatically improved the prognosis for these patients. It is important for clinicians to appreciate the multisystem sequelae of end-stage liver disease, to assess risk and manage patients appropriately. Recognition of severe disease is crucial; improved perioperative care has not significantly reduced operative mortality. These patients should be referred for transplant assessment or, if surgery for unrelated conditions is considered, should be managed in specialist centres.

Risk assessment

The Child–Pugh classification of liver disease (Figure 1) was originally described to assess operative risk in cirrhotic patients undergoing surgery for variceal bleeding. Its use has extended to predict outcome in cirrhotic patients for all types of surgery. Others have studied the effects of systems failure on outcome in patients with severe liver disease (Figure 2). Optimizing treatable complications (e.g. ascites) may decrease mortality significantly. Causes of death in these patients are sepsis, renal failure, bleeding, hepatic failure and encephalopathy. Poor nutrition, portal hypertension with ascites and encephalopathy herald poor prognosis for any surgery in these patients. However, recent work suggests that cirrhotic patients with good function who are well compensated (i.e. Child–Pugh Grade A) are good candidates for certain types of surgery (e.g. liver resection for hepatocellular carcinoma or portosystemic shunt surgery).

Figures 1 & 2

Extrahepatic effects of end-stage liver disease

Cardiovascular system: in end-stage liver disease the systemic circulation is characterized by various pathological changes. Peripheral vasodilatation and shunting (cutaneous, intrapulmonary, portopulmonary and pleural) result in increased cardiac output. This can mimic the hyperdynamic picture of a septic state. Activation of the renin–aldosterone–angiotensin (RAA) system causes an increase in plasma and extracellular fluid volume, though effective circulating volume is reduced. Cirrhotic cardiomyopathy may be masked by the reduction in afterload, and is difficult to detect by non-invasive preoperative investigations. Pulmonary hypertension is also seen and is a rare cause (<1%) of right ventricular failure. Cardiac arrhythmias also occur, associated with cardiomyopathy or electrolyte abnormalities such as hypomagnesaemia and hypokalaemia. The responsiveness to catecholamines is reduced.

Respiratory system: respiratory compromise may result from restrictive lung disease caused by ascites or pleural effusions, the hepatopulmonary syndrome, pulmonary hypertension, defects in alveolar oxygen diffusion or pulmonary manifestations of systemic disease (e.g. alpha1-antitrypsin deficiency, autoimmune disease). Several factors dispose the cirrhotic patient towards hypoxaemia: a rightward shift in the oxygen-dissociation curve (due to decreased levels of 2,3-diphosphoglycerate [2,3-DPG]), intrapulmonary shunting due to capillary vasodilatation and restrictive defects due to large volume ascites and pleural effusions. These effects are compensated for by the raised mixed venous oxygen saturation consequent on poor oxygen extraction and the raised resting cardiac output. All patients with end-stage liver disease and a partial pressure of oxygen (pO2) less than 9 kPa should be considered hypoxic. In patients with the hepato-pulmonary syndrome (chronic liver disease, increased alveolar–arterial gradient while breathing room air, and evidence of intrapulmonary vasodilatation) transplantation is associated with a good outcome and improvement of hypoxia as vascular remodelling occurs. By contrast, in patients who have portopulmonary hypertension and an increase in pulmonary vascular resistance, transplantation does not result in improvement. Severe pulmonary hypertension (mean pulmonary arterial pressure >50 mmHg) is associated with right ventricular failure and sudden cardiac death; mortality is 100% in this group. Preoperative therapy with prostacyclin and nitric oxide may improve outcome in this group though treatment needs to continue long term, suggesting that the benefit is obtained from vascular remodeling not just a decrease in pulmonary pressures. Large volume ascites also increases the risk of pulmonary aspiration.

Renal and endocrine system: some renal dysfunction is common in patients with cirrhosis, portal hypertension and ascites. Compensatory mechanisms to restore mean arterial pressure in cirrhotic patients result in activation of the RAA system with sodium and water retention and the development of ascites. Non-osmotic hypersecretion of vasopressin occurs due to the relative decrease in central blood volume due to splanchnic pooling. As the severity of the disease progresses, disproportionate water retention occurs and dilutional hyponatraemia results. At its most severe this can lead to the ‘hepatorenal syndrome’. This represents severe renal vasoconstriction. Renal angiography in this setting demonstrates absent cortical blood flow. Hepatorenal syndrome is characterized by a rapid deterioration in renal function associated with low urinary sodium excretion. Strategies to improve renal function in this setting include the use of splanchnic vasopressors (e.g. terlipressin) with volume resuscitation, transjugular intrahepatic portosystemic stent (TIPSS) placement to reduce portal hypertension, and liver transplantation. Prognosis is poor for hepatorenal syndrome. Renal function is difficult to assess in end-stage liver disease because reduced muscle mass and hepatic synthesis of creatine reduce serum creatinine inappropriately. Creatinine clearance overestimates glomerular filtration rate, and inulin or 51Cr EDTA clearance remain the gold standard.

Endocrine dysfunction is common in end-stage liver disease, due to inappropriate activation of some systems (RAA system, vasopressin release), abnormal responses (insulin resistance), over-secretion of growth hormone and glucagon, and abnormal metabolism (steroid hormones). This leads to clinical syndromes of insulin resistance and impaired glucose metabolism, a shift towards lipid utilization as a preferred energy substrate, and depletion of glycogen stores. Hypoglycaemia in cirrhosis is uncommon and a poor sign. The abnormal metabolism of sex hormones leads to feminization, gonadal atrophy and gynaecomastia in men, and amenorrhoea in women.

Gastrointestinal system: advanced cirrhosis is characterized by portal hypertension and portosystemic shunting, typically resulting in oesophageal varices, which can cause massive gastrointestinal haemorrhage. Varices may also be present on the anterior abdominal wall and may cause severe blood loss during laparotomy. Ascites develops due to a combination of portal hypertension, poor synthetic function with hypoalbuminaemia and the pathophysiological activation of the RAA system. The volume of ascites may be such that intra-abdominal pressure exceeds renal perfusion pressure causing deterioration in renalfunction. For this reason, draining ascites (especially if intraabdominal pressure is >25 mmHg) is regaining popularity, especially in those resistant to diuretic treatment. Nutritional abnormalities are common in these patients and associated with peripheral and hepatic insulin resistance and a poor outcome. Glucose utilization is impaired and lipid utilization is increased in fasting and fed conditions. Hypermetabolism seems to predate the malnutrition seen with increasing severity of cirrhosis and in contrast to earlier regimens a high-protein, high-calorie intake, taken little and often, seems to prevent the catabolic state without increasing the incidence of hepatic encephalopathy.

Haematological system: the liver has a central role in the control of coagulation. Impairment of haemostasis is common in liver disease, bleeding is a leading cause of death in cirrhotic patients. The liver is the main site of synthesis of all coagulation factors except von Willebrand’s factor. It is also the key site for clearance of activated clotting factors and plasminogen activators; the coagulation state depends on the balance of hepatic synthesis of clotting factors and clearance of activated clotting factors, their inhibitors and fibrinolytic proteins. Failure of bile salt secretion results in poor absorption of vitamin K and low levels of the vitamin K-dependent clotting factors (II, VII, IX, X), but inactive prothrombin complexes are present in liver disease without vitamin K deficiency suggesting an acquired defect in activation.

Many platelet abnormalities occur in patients with liver disease. Thrombocytopenia may result from hypersplenism secondary to portal hypertension in cirrhotic patients, bone marrow suppression, abnormalities in platelet metabolism or autoimmune causes. In alcohol-related liver disease thrombocytopenia may result from folic acid deficiency. Qualitative platelet dysfunction is also seen in liver disease, with impaired aggregation and clot retraction.

CNS: hepatic encephalopathy is the decrease in conscious level seen in association with severe liver disease. In the early stages a reversal of the sleep–wake cycle is seen with patients sleeping during the day. As encephalopathy advances, subtle changes in intellectual function occur with confusion, memory loss and irritability being common. Finally, changes in conscious level are observed. Work in liver failure shows intracranial hypertension, brain oedema and herniation with altered perfusion. Encephalopathy can be precipitated by a variety of factors including hypovolaemia, sepsis, gastrointestinal haemorrhage and hypoglycaemia. The final common pathway in the aetiology of brain oedema may be increased cerebral blood flow with consequent increased ammonia uptake across the blood–brain barrier. Hyperventilation and consequent alkalosis increase the ammonia available to cross the blood–brain barrier.

Immune system: patients with advanced cirrhosis are relatively immunocompromised. Low complement levels, loss of effective white cell opsonization and dysfunctional macrophage phagocytosis contribute to anergy, leading to high levels of bacteraemia. Spontaneous bacterial peritonitis is common in end-stage liver disease. Increasingly, Gram-positive bacteria, which may be multiresistant, are being cultured in these patients.

© 2003 The Medicine Publishing Company Ltd

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