Physiological consequences of acute liver failure

Question 30 from the second paper of 2010 and Question 24.2 from the first paper of 2022 asked about the complications of acute liver failure. Acute liver failure is a major inconvenience, adversely affecting all the organ systems. Among the possible complications, one might expect ARDS, circulatory collapse from SIRS, encephalopathy and raised ICP, a metabolic acidosis, renal failure due to hepatorenal syndrome, bone marrow failure, coagulopathy and immune suppression.

There is a brilliant article by Wang et al (2013). which outlines all the possible and impossible complications. It would be the first choice for a time-poor exam candidate. Somebody with a little extra time may want to also read the review article by Bernal et al (2010).  The liver enthusiast with infinite resources may already be intimately familiar with the "Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure (2011)", which has informed much of the ensuing discussion.

In summary, here is a short list of acute liver failure complications for the exam:

SIRS, vasodilation and circulatory collapse

Acute liver failure patients frequently develop a severe vasoplegia,. Characteristically, this gives rise to a hyperdynamic circulation. This is well studied in patients who undergo liver transplantation, which is a pretty good model of acute liver failure (consider that the cadaveric graft had undergone an ischaemic injury). Siniscalchi et al (2010) demonstrated that patients who become haemodynamically unstable following the reperfusion of a cadaveric transplant tend to have a hyperdynamic circulation with high cardiac output, low MAP, and low systemic vascular resistance.

This vasoplegia is  thought to be due to the activation of induceable nitric oxide synthase by exposure to bacterial endotoxin of enteric origin. Iwakiri et al (2006) brought the matter together nicely in their article for Hepatology, even though much of the discussion was about chronic liver disease. An acute liver failure model can be seen in a 2001 article by Han. In summary, nitric oxide synthase is activated by the increased availability of endotoxin which results from portal blood being shunted past the liver and into the systemic circulation. In acute liver failure, the process is analogous. The swollen necrotic liver obstructs portal venous flow, and shunts open. Even if there is little shunting, one must consider that the acutely failing liver is unlikely to perform the usual tasks of clearing endotoxin from portal blood, and it ends up in the systemic circulation. This has been demonstrated convincingly in in rats. The rats which had a total colectomy prior to their acute liver injury had serum endotoxin levels indistinguishable from baseline, and did not go on to develop vasodilated shock.

Also, some of the vasodilated sepsis-like state is due to actual sepsis. Rolando et al (2001) have investigated this feature of acute liver failure among a cohort of 887 patients admitted to a single centre over an 11 year period. Of these, about 57% ended up manifesting some sort of SIRS, be it infective or not. Among the "severe sepsis" patients mortality was 59%; it increased to 98% if the patients were also shocked.

Acute lung injury and other causes of hypoxia

ARDS will develop in the course of the whole SIRS process, and it will look and behave just the same as it would in any other SIRS state. In that regard, ARDS is ARDS. The major difference in the setting of liver failure is the poor tolerance for high CO₂, as the patients will have ammonia-induced increased ICP. Thus, "permissive hypercapnea" is out of the question.

Non-ARDS causes of hypoxia may also be involved. For example, Karcz et al (2012) identified several other causes of respiratory failure and impaired gas exchange in patients with advanced liver disease:

• Portopulmonary shunt
• Hepatopulmonary syndrome
• Hepatic hydrothorax
• Impairment of ventilation by massive ascites
• Reversal of hypoxic pulmonary vasoconstriction by SIRS

Hepatic encephalopathy and raised intracranial pressure

This topic is discussed at length elsewhere, in the chapter on hepatic encephalopathy

Briefly, I will quote the Parsons-Smith Scale of Hepatic Encephalopathy, in its modified form.

There is also the West Haven Criteria:

The key feature with which one must become familiar is the decision to monitor intracranial pressure. Our experience in this is guided by the neurosurgical experience in traumatic brain injury, and the existing guidelines are analogous to the guidelines for the management of raised ICP in trauma patients. There are several differences in the approach:

• Grade 3-4 by the Parsons-Smith scale deserves an ICP monitor, IF:
  • the patient is young
  • the presentation is "hyperacute"
  • the serum ammonia is over 150mmol/L (anything over 200 is associated with cerebellar herneation)
• ICP monitoring should be performed with a parenchymal device, such as a Codman catheter (as the risk of bleeding with these is much less than with an EVD)

Hypercatabolic state and increased nutritional requirements

Living without a working liver is hard work. At least in paracetamol overdose with fulminant hepatic failure, the metabolic rate seems to be increased by about 30%, which is probably due to the massive SIRS response, and is therefore analogous to sepsis. Thus, one ought to feed these people a proportionately increased daily caloric load. A guidelines statement from Madrid (Gonzalez et al, 2011)  recommended a daily caloric supply of 25-40 kcal/kg/day.

There is no data to recommend any specific change in macronutrient: apparently these people can handle the same amount of fat as you and me (but one should probably give no more than 1g/kg/day). Moreover, it seems that the protein requirements are also no different. The conventional wisdom that more protein means more encephalopathy has been challenged, and these days we should probably feed these patients an appropriate amount of protein. The idea of using branched-chain amino acids is still  being thrown around, but most studies in support of this have been in a population of chronic liver disease outpatients, so it is difficult to extrapolate the proposed benefits.

Metabolic acidosis (with raised lactate)

Yes, the lactate is high. In these people, with their failure of metabolic function, lactate levels may remain in the late teens even as the shock state resolves and the acute illness subsides. The rate of lactate metabolism is simply too low to keep up with even trivially increased prodction.

So, three questions are important:

1. Should we freak out over the lactate in liver disease?
2. Should administration of exogenous lactate be limited?
3. Is hyperlactataemia harmful in and of itself?

1) Yes, lactate is a useful marker in liver disease. But rather than a biomarker tissue perfusion problems, it should probably be interpreted as a marker of liver failure. The higher the lactate, the worse the liver. For instance, Bernal et al (2002) had found that a lactate of over 3.5mmol/L identifed early non-survivors as well as the King's College Criteria. In answer to the question: yes, it is important to monitor lactate, and one should not ignore it.

2) Exogenous lactate should be limited. In his chapter for Ronco Bellomo and Kellum's Critical care Nephrology, Karl Reiter comments that "it is probably wise to avoid lactate replacement solutions in patients with all grades of hepatic insufficiency". However, he also confesses that the data is not very solid. One quoted study showed worsening lactate; another crossover study could not find any difference between bicarbonate and lactate buffers (McLean et al, 2000).

3) Lactate in high concentrations is probably completely benign.  Wang et al mention that "it can affect circulatory function and aggravate cerebral hyperemia", but no reference is offered in support of this. Fortunately, we have cruel dog studies to inform us. In the eighties, Arieff et al infused lactic acid into some dogs, hepatectomised others, and fed vast amounts of phenformin to a third group. After 3 hours of infusion, mean lactate was 5.6 mmol/L and mean pH was 7.17; however in these animals the cardiac output was no different to controls (about 3.0 L/min). In contrast, the hepatectomised dogs had a gross haemodynamic derangement with a cardiac output around 1.0 L/min. Clearly, its not the lactate at fault.

Hypoglycaemia

Live disease patients are at risk of hypoglycaemia. There are several reasons for this:

• Decreased glycogen stores
• Impaired glycogenolysis
• Impaired gluconeogenesis

Impaired glycogen storage is frequently blamed for the hypoglycaemia of liver disease. The liver is only one of the stores of glycogen, and in fact there is probably more glycogen stored in the muscle, but it is fairly well trapped there. The liver and kidneys are the main sources of glucose-6-phosphatase, an enzyme which is required to liberate glucose for systemic use; muscle tissue largely lacks this enzyme (Van Schaftingen & Gerin, 2002). Hepatic injury will therefore produce hypoglycaemia by several mechanisms among which decreased shelf space for glycogen is only one factor (Arky, 1989)  What glycogen remains ends up not being hydrolysed by glycogenolysis enzymes; an what glycogen gets hydrolysed will not enter the systemic circulation because the dying hepatocytes are less concerned with maintaining healthy levels of  glucose-6-phosphatase or conducting synthesis of new glucose from precursors.

Impairment of adrenal function

The shocked patient with acute hepatic failure may be hypotensive because of their impaired response to ACTH. One can demonstrate this in the classical sense, by performing a short synacthen test (the normal dose, 250 μcg). These people will benefit from hydrocortisone. Harry et al (2003) found abnormal short synacthen test results in 62% of their liver-dysfunctional cohort. It was  a matter similar to the relative adrenal insufficiency seen in sepsis, except none of the patients had positive blood cultures.

Renal failure and hepatorenal syndrome

This is discussed in great detail in the chapter on hepatorenal syndrome. Suffice to say, it is a diagnosis of  exclusion, and there are several diagnostic criteria to remember:

The management of confirmed hepatorenal syndrome would consist of

• Albumin
• Noradrenaline
• Terlipressin
•  Octreotide
• TIPS procedure
• Liver transplantation

(the links point to the relevant subsections of the abovementioned chapter).

Of course not all renal failure in acute liver disease is going to be due to this specific pathological process. There is plenty of other reasons for the kidneys to fail, and according to Wang et al the incidence of renal failure is about 50-80%. CRRT is usually the answer, because these people are usually so haemodynamically fragile that SLED cannot be performed.

Can I use citrate, you might ask. Usually, one would have to say no: it is a classical contraindocation for citrate. Without a liver, citrate remains in the patient's circulation, and metabolic acidosis will ensue. However,   Devauchelle et al (2012) has reported on three cases of CRRT with citrate anticopagulation being used safely. The key to success is to pay close attention to the total-to-ionised calcium ratio, and to have fast effluent flow rates so as to increase cqalcium-bound citrate clearance from the circuit.

Coagulopathy of acute liver failure

When one uses the term "coagulopathy", one typically refers to a tendency of increased bleeding. In acute liver failure there may also be a prothrombotic tendency because of the failure of Protein C and Protein S synthesis. Sure, the coags look completely deranged, but general one might be surprised as to how stable to coagulation system is. All the factors are being depleted at once, after all - both the procoagulant and the anticoagulant factors.

A demonstration of this phenomenon requires tests of whole-blood clotting function, rather than unidimensional tests of specific pathways. For example, Strvitz et al (2012) did a bunch of TEGs in acute liver failure patients all of whom had a raised INR (mean = 3.4, with a range from 1.5 to 9.6). In spite of this, mean TEG parameters were normal. Measures of clot strength were worst in thrombocytopenic patients, and - weirdly - maximum amplitude increased in acute liver failure, which was attributed to an unequal decrease in anticoagulant and fibrinolytic proteins.

In summary, the risk of bleeding with acute liver failure is probably overestimated by the INR.

Bone marrow suppression

Ranging from mildly depressed function to complete failure with aplastic anaemia, bone marrow dysfunction is a known association of acute liver disease. Tung et al (2000) reported on this phenomenon in the paediatric population, where the incidence was about 10%. It is thought that this develops as the result of infection-triggered cytokine production that inhibits bone marrow stem cells. It is seen more commonly in acute hepatitis. Tung and colleagues reported good results from the use of anti-thymocyte globulin (ATG).

Impairment of immune function

The following immunological problems have been identified in acute liver failure patients:

• Complement deficiency due to impaired synthesis (Wyke et al, 1980)
• Defective opsonisation as the consequence of decreased complement
• Impaired phagocytosis of encapsulated organisms due to defective opsonisation)
• Impaired chemotaxis
• Impaired neutrophil function (Clapperton et al, 1997)

Sepsis is common. Oh's Manual recommends antifungals routinely for those awaiting transplant. Prophylactic antibiotics seemed to decrease the risk of septic episodes in the cohort studied by Rolando et al (2001). However, this did not translate into an improvement in mortality. The AASLD statement from 2011 quoted this study when they made their recommendation to not offer routine antibiotic prophylaxis to all acute liver failure patients.