Adapted from Schindl MJ, Redhead DN, Fearon KC et al. The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection. Gut 2005; 54:289–96. With permission from the BMJ Publishing Group Ltd.

Common causes of acute liver failure: hepatic insufficiency following liver resections

Liver resection is the only treatment with the potential to cure patients with cancers that have originated in the liver itself (primary liver cancer) or that have originated elsewhere and have subsequently spread to the liver (metastatic liver cancer). Equally, it is a preferred therapy in patients with tumours in the liver that are benign, but with the potential of malignant transformation (uncertain benign primary liver tumours). Liver resection of even major parts of the liver (up to 70%) is feasible, because the liver has a remarkable capacity to regenerate. Within 6–8 weeks following 60–70% hepatectomy, the liver has regained nearly its original size and weight.

The most common cause of metastatic liver cancers is primary colorectal cancer, and it is estimated that in the West there is a yearly incidence of 300 new cases of liver metastases from colorectal origin per million population. The current estimate is that this should lead to approximately 100–150 patients per million eligible for liver resection for this indication. To this should be added the patients with primary benign and malignant liver tumours, and hence about 150–200 liver resections should probably be performed per million population each year.

Ever since the first liver resection by Langenbuch in 1887, this procedure has remained a major undertaking and even in the recent past, liver resection was still a dangerous surgical procedure with a high mortality of 20–30% in the 1970s. This was mainly due to excessive intraoperative bleeding but, over the subsequent decades, the procedure has become increasingly safe due to improvements in surgical and anaesthetic techniques. At present, mortality rates are reported to be well below 5%. Currently, the single most important cause of lethal outcome following surgical removal of major parts of the liver is liver failure. For this reason, many researchers and clinicians have attempted to design methods to identify patients at risk of liver failure (and hence mortality) following liver resection. The development of such a method has been hampered by several factors, as outlined below.

The critical point determining lethal outcome following liver resection has been a failure of the residual liver to function properly. Therefore, focus in this research area has always been in identifying a single liver function test that identifies those patients that have a liver with limited function. This has proven exceedingly difficult, and hence such a test is not available for a number of reasons.

First, as outlined above, the liver has a remarkable capacity to regenerate very rapidly, which underlines that there is tremendous overcapacity of several liver functions. In this context, it is known that it is entirely safe in most instances to resect 50% of the liver, because the residual half liver will simply take over all vital liver functions such as clearing bacteria, urea synthesis and synthesis of crucial proteins. From this, it has been estimated that a crucial liver function such as urea synthesis has an overcapacity of 300%, which implies that a static preoperative liver function test will be unable to assess this particular function. An alternative and innovative strategy would be to give a challenge to the liver and measure the ability of the liver to respond or cope – a dynamic test.

The critical minimum residual liver volume has been estimated to be approximately 25% after resection.²

The second crucial problem has been that there is only a poor correlation between volume and function. However, it is still unclear why some patients with smaller hepatic remnants do not develop liver failure whilst some with greater residual volumes do. These observations suggest, however, that peri- and intraoperative events superimposed on the innate hepatic capacity to withstand injury play a role. Hepatic insufficiency in this situation may arise either if not enough liver volume is left after partial hepatectomy or if the residual volume does not function properly. A functional limitation may arise, for example, in patients that have received aggressive chemotherapy in order to reduce the number and size of metastases prior to surgical treatment by liver resection. One of the factors contributing to defective defence may be preoperative fasting,³ but equally prior chemotherapy and pre-existent steatosis may play a role.

A third important aspect is that during liver surgery deliberate hypotension and temporary hepatic blood inflow occlusion (the so-called Pringle manoeuvre) are used by many surgeons to reduce blood loss during liver surgery (15 minutes ischaemia, 5 minutes reperfusion (15/5 Pringle)). Other surgeons do not use this manoeuvre, assuming that it causes oxidative stress and ischaemia/reperfusion (I/R) injury.⁴^,⁵ There is little doubt that this procedure does cause oxidative stress and I/R injury; however, the consequence of this is variable. In a situation where defence mechanisms against oxidative stress are deficient it may adversely affect liver function. In this situation hepatic steatosis may constitute an additional predisposing factor to damage by ischaemia/reperfusion.

Ischaemia/reperfusion is, on the other hand, the basis of ischaemic preconditioning, a process in which temporary clamping and release of the liver blood flow has been shown to be beneficial in terms of increasing resistance to subsequent injury.⁶

In this situation it is assumed that defence mechanisms against oxidative stress are adequate and are indeed enhanced by short-term I/R injury.⁷

The above three factors explain why it has been exceedingly difficult hitherto to design a proper liver function test that reliably singles out those patients at risk of liver failure following liver resection. The term ‘liver function’ is a rather crude denominator for a range of functions that includes ammonia detoxification, urea synthesis, protein synthesis and breakdown, bile synthesis and secretion, gluconeogenesis and detoxification of drugs, bacteria and bacterial toxins.

Chronic liver failure

The clinical signs of chronic liver failure are often insidious and can also be related to the type of disease. Cirrhosis is associated with a failure of hepatic function and the consequences of increased hepatic vascular resistance. Metabolic impairment is manifest by jaundice, coagulopathy, impaired ammonia clearance and encephalopathy, hypoalbuminaemia and oedema. The presence of increased vascular resistance is associated with the development of splenomegaly, ascites and gastro-oesophageal or abdominal wall varices. The slow progression of many chronic liver diseases, over years, implies a gradual, almost incremental, loss of liver cell mass or function. There are many causes of liver failure, including hepatitis B and C virus, autoimmune diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis, alcoholic liver disease, Wilson’s disease, α₁-antitrypsin deficiency and others. All are associated with chronic or repeated cell injury and attempts at repair. The fibrosis and scarring associated with this regeneration and repair lead to the clinical condition termed cirrhosis, with a typically small shrunken irregular liver and an increased risk of cancer.

The Child–Pugh score for chronic liver disease ⁸ has served as a useful means of categorising patients based on the severity of their liver disease. It employs five clinical measures of liver disease and each measure is scored 1–3, with 3 indicating the most severe derangement (Table 1.1).

Table 1.1

Child-Pugh score for chronic liver disease

Metabolic liver function

The liver plays a central role in fat, carbohydrate and protein metabolism, as well as in acid–base homeostasis. In the context of liver failure, disturbances of fat metabolism are probably not crucially important. With respect to carbohydrate metabolism, it is well known that the liver plays a central role in the conversion of lactate to glucose. Part of this lactate is formed due to anaerobic metabolism of, amongst others, glucose in skeletal muscle. This metabolic route of glucose to lactate (muscle) and then back to glucose (liver) is very important for glycaemic homeostasis and is called the Cori cycle. Failure of the liver will be witnessed by lactic acidosis and hypoglycaemia.

Next to its role in carbohydrate metabolism, the liver plays a central function in nitrogen homeostasis. Hepatic synthesis and breakdown of proteins and amino acids, and detoxification and clearance of nitrogenous waste products of amino acid and protein metabolism in other organs are of central importance. For example, the gut uses the amino acid glutamine as a fuel for enterocytes, which give rise to the production of waste end-products of intestinal metabolism, like ammonia. This ammonia is then transported by the portal vein to the liver, where it is detoxified by the formation of urea.

Liver failure gives rise to multiple abnormalities in nitrogen metabolism, some of which are thought to play a crucial role in the characteristic syndrome of hepatic encephalopathy that accompanies liver failure. Hepatic encephalopathy is a reversible neuropsychiatric syndrome, with a probably multifactorial cause.⁹ The current belief is that ammonia is one of the key components in the aetiology of hepatic encephalopathy¹⁰ because liver failure is usually associated with moderate to severe hyperammonaemia. Hyperammonaemia leads to increased brain uptake of ammonia, followed by detoxification of ammonia in the brain by coupling to glutamate to form glutamine. This process consumes glutamate (an important excitatory neurotransmitter) and leads to the formation of glutamine, which acts as an osmolite causing brain oedema.

One other well-known metabolic abnormality during liver failure is an imbalance in plasma amino acids, notably the ratio between the branched chain amino acids (BCAAs) and the aromatic amino acids (AAAs).

Some 30 years ago, Fischer and colleagues published their ‘unified hypothesis on the pathogenesis of hepatic encephalopathy’,¹¹ based on the observation that, during hepatic failure, plasma levels of BCAAs were decreased and the AAAs were increased.^11–13

These changes in plasma levels were thought to be caused by increased BCAA catabolism in muscle and decreased AAA breakdown in the failing liver.¹⁴ A reduction in the insulin–glucagon ratio in this situation may play a key role in disturbing the balance between anabolism and catabolism. Accumulation of AAAs in the circulation in combination with the increased breakdown of BCAAs, particularly in skeletal muscle, would, according to this hypothesis, give rise to a decrease in the BCAA to AAA ratio, the so-called Fischer ratio. The increase in plasma AAAs in combination with increased blood–brain barrier permeability for neutral amino acids has been suggested to contribute to an increased influx of AAAs in the brain, since they compete for the same amino acid transporter. This, in turn, would lead to imbalances in neurotransmitter synthesis and accumulation of false neurotransmitters such as octopamine in the brain, which may contribute to hepatic encephalopathy.¹⁵