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Acute liver failure and acute kidney injury: Definitions, prognosis, and outcome
Wodzimirow, K.A.
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Wodzimirow, K. A. (2013). Acute liver failure and acute kidney injury: Definitions, prognosis, and outcome
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Download date: 14 Jun 2017
Chapter 1
General introduction and outline
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This thesis addresses aspects of definitions, prognostic indicators and their association
with adverse events, mainly mortality in two domains. The first is severe liver failure
(namely acute liver failure and acute-on-chronic liver failure) and the second is acute
kidney injury. Below we first describe aspects related to these domains and then outline
the thesis.
Part one - Severe liver failure
No life without a liver. For Homo sapiens and many other species the liver is an
indispensable organ. It is the largest gland in the human body and behaves as a
biochemical factory with a large spectrum of functions: bile production, detoxification of
endogenous and exogenous toxins, protein synthesis, homeostasis of carbohydrate, lipid
and amino acid metabolism, hormone-, thermo- and immune regulation and it has a
large storage capacity for glycogen, vitamins and minerals.
When the liver is no longer able to perform its normal functions due to disease or loss of
a large amount of functional parenchyma we speak about severe liver failure (SLF).
There are three syndromes of SLF to be distinguished:
- Acute liver failure (ALF), when SLF develops without pre-existing liver disease
- Acute-on-chronic liver failure (ACLF), when liver function of chronic liver disease
severely decreases due to a precipitating event
- Decompensated cirrhosis as an end-stage of progressive chronic liver failure (CLF)
This thesis focuses on ALF and ACLF as acute syndromes of SLF.
There is a large amount of literature about SLF, however there is no
consensus in the definitions used for the conditions. Acute liver failure (ALF), also
known as fulminant hepatic failure (FHF) has been first defined in 1970 by Trey and
1
Davidson as the occurrence of hepatic encephalopathy as a consequence of severe
liver injury developing within 8 weeks of the onset of symptoms in patients without
preexisting liver disease. Since then many other definitions have appeared in literature
describing in addition to cerebral dysfunction (hepatic encephalopathy) other aspects of
the syndrome e.g. coagulation abnormalities and jaundice occurring within a number of
2
weeks and in absence of underlying liver disease . There are various causes for ALF:
acute
viral
hepatitis
(e.g.
HAV,
HBV,
HCV,
Epstein-Barr,
herpes
simplex),
acetaminophen and other hepatotoxic drugs and amanita phalloides, autoimmune
hepatitis, vascular and metabolic disease (e.g. Budd-Chiari syndrome, and Wilson's
2
disease and fatty liver of pregnancy) .
-8-
ACLF is another syndrome in which two insults operate on the liver
simultaneously, one of them on-going and chronic in nature and the other an acute intraor extrahepatic event. Although it is an increasingly recognised entity, there is no
3
consistent definition of ACLF in the literature . The chronic condition underlying ACLF
disease (mostly cirrhosis) is due to: hepatitis B, C, alcohol, Wilson's disease,
autoimmune, and cryptogenic. The acute event is usually one of: acute viral or toxic
hepatitis (e.g. excessive use of alcohol, drugs), upper gastrointestinal bleeding, and
4
sepsis . Although ACLF remains a clinical distinct entity, its evidence-based definition
and diagnostic and prognostic criteria are limited due to lack of prospective data 3.
Different definitions have been published in the literature but there is no review
summarising them and describing their inter-relationships and range of their
variability.
Liver failure, whether acute or acute-on-chronic, is an important cause of
morbidity and mortality. The lack of liver detoxification, metabolic and regulatory
functions lead to renal failure, hepatic encephalopathy, systemic immune response
(SIRS) and systemic haemodynamic dysfunction and culminates in multi-organ failure
5
(MOF) . Severe liver failure is a life-threatening condition with inordinately high mortality
of 50-90% in case of ACLF
5
and in case of ALF the most frequently reported mortality
6
7
exceed 80% reaching even 100% .
ALF and ACLF are medical emergencies that require hospitalisation and urgent medical
care. In some cases survival can be achieved with intensive medical care including liver
support devices, but in most cases a liver transplantation (LT) is the only way to save
patient's life. LT is a definitive treatment for those patients who do not recover, and its
use has markedly improved the overall survival to above 60% and in individual centres
even to 80%-90%
6
in case of ALF. There is however scarcity of liver donors. Data on
4
liver transplantation in ACLF are limited . SLF, whether ALF or ACLF, might be
reversible in specific cases. An early and proper identification of those patients that
require transplantation from those with a potential for reversibility of liver functions and
survival with only intensive medical care is crucial. Timely identification of such patients
would help to prevent transplantation and thus the need for lifelong immunosuppressive
therapy. This is also of great importance in light of the worldwide shortage of donor
livers. Identification of (bio-)markers that are associated with patient outcome remains
challenging. There is no inventory of tools to prognosticate (predict) outcomes in ACLF,
8
which are still subject of on-going research . Specifically, there is no literature
evaluating prognostic indicators used for ACLF and assessing their predictive
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value. There is wide spectrum of (bio-)markers that have been used to predict outcome
in ALF and specific prognostic models have been developed for ALF of different
etiologies, however universally accepted prediction criteria do not exist. The most widely
accepted prognostic models such as the King's College Criteria (KCC), used separately
for non-acetaminophen and acetaminophen patients; the Clichy criteria; and the Model of
End-Stage Liver Disease (MELD) have shown inconsistent prognostic performance. A
number of alternative prognostic models have been proposed in the literature, however
they did not find wide applicability. There is no literature identifying such models and
evaluating their quality. Consequently a need for a better prognostic index remains.
There is also lack of review summarising this wide range of prognostic indicators
along with evaluation of their predictive value. Such a review could provide a good
starting point for development of valuable prognostic indices.
In clinical practice prognostic information is derived from clinical, laboratory,
histological and radiological investigations. Ideally, a predictive method should have
potential advantages over the conventional medical tests, namely, it should be noninvasive, available at the bed-site, low cost, safe and provide real-time results. Such
requirements can be met by the discoveries known from antiquity that led to current
understanding of the diagnostic potential of exhaled breath, following Hippocrates - “You
9
can learn a lot just by smelling your patients with unaided nose” . Odour of the breath
can be altered in individuals by certain diseases. Some diseases have been associated
with characteristic smell e.g. diabetes with acetone odour; uremia with a fishy odour;
intestinal obstruction or an oesophageal diverticulum with a feculent odour and lung
abscess or an empyema with foul, putrid odour. Patients with liver failure produce odour
of musty fish or raw liver
9
. In recent years, exhaled breath analysis has been
increasingly studied as an alternative to the invasive methods of blood testing. Devices
called electronic noses (e-noses) have been applied in clinical medicine to diagnose
diseases from human samples, such as blood, urine, sweat, or breath
10
. The research
and development of e-nose applications in the biomedical field have accelerated over the
last decades. The development of e-nose applications in the healthcare industry has
grown rapidly probably due to economic advantages favoring these technologies in the
healthcare industry and greater economic incentives for the development and use of
cheaper, high-performing electronic-sensor instruments
10
. Although the underlying
technology of e-noses varies, the general principles are similar to those of the human
nose
11
. E-noses have been applied for diagnosis of diabetes
track disease
13-14
, lung disease
15-16
12-13
, renal and urinary
, Alzheimer and Parkinson disease
- 10 -
17
, and different
forms of cancer (lung, breast, colorectal, prostate, liver)
18-19
. E-nose technology has
not been applied to ALF yet. The demands and expectations on functional
requirements of biomedical tools that are used in daily healthcare applications are
increasing, in ALF and other conditions. Improvement of performance and effectiveness
of such tools as well as providing rapid and accurate results while being cost-effective
continue to be the subjects of on-going study.
Part two - Acute kidney injury
No life without kidneys. Although kidneys are of relatively small size, they receive a huge
amount – approximately 20%, of the blood pumped by the heart
20
. The kidneys are
crucial for maintenance of homeostasis. They rid the body of waste materials that are
either ingested or produced by metabolism (such as urea, creatinine or toxic substances)
and control the volume and composition of the body fluids. They perform the regulatory
function by filtering the blood plasma (approximately 180 Liter per day) and removing
substances from the filtrate at variable rates, depending on the needs of the body.
Additional functions of the kidneys include the regulation of arterial blood pressure and
the production of the hormones.
Acute kidney injury (AKI) is the new consensus term for acute renal failure. It refers to a
clinical syndrome characterized by a rapid (hours to days) decrease in renal excretory
function, causing accumulation of waste products and disorders of fluid balance,
electrolytes and acid-base
21 34
,
. AKI is a frequent complication in critically ill patients in
the intensive care unit (ICU) and is associated with high morbidity and mortality,
particularly if renal replacement therapy is being required
22
. In ICU patients AKI rarely
presents as an isolated organ dysfunction, but rather as a component of the multiple
organ dysfunction syndrome, following a broad spectrum of diseases, such as severe
sepsis, pancreatitis or cardiogenic shock 21, 23. Over the last few decades, more than 35
different definitions have been used to define AKI making it difficult or even impossible to
compare the various studies focusing on AKI
24
. In May 2004 the Acute Dialysis Quality
Initiative proposed a consensus graded definition, called the RIFLE, the initials reflecting
the terms Risk, Injury, Failure, Loss and End Stage in relation to kidney function 25. This
system relies on changes in the serum creatinine and/or urine output. The RIFLE
classification is the first widely accepted definition for AKI, however many studies have
applied RIFLE, not concordantly with the definition, without the use of urine output.
There is no literature evaluating the consequences of using different definitions
on the outcomes. The traditional biomarkers used to define AKI (creatinine, urea, urine
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output) have several shortcomings in establishing an early and sensitive diagnosis of AKI
26
. To improve early recognition and intervention in AKI, other biomarkers are needed
27 28
and remain a subject of on-going research ,
.
Objective and outline of the thesis
The objective of this thesis is to investigate definitions, prognostic indicators and their
association with adverse events, mainly mortality for acute liver failure (ALF), acute-onchronic liver failure (ACLF) and acute kidney injury (AKI). ALF and ACLF are addressed
in the first part of the thesis, and AKI in the second part. The studies address the lacunas
highlighted in the description of severe liver failure and acute kidney injury.
The first part of the thesis has three aims:
Aim 1) investigating definitions (Chapter 2 and 5), prognostic indicators (Chapter 3 and
5) and models (Chapter 4) and their association with morbidity and mortality (Chapters 2,
3, 4, and 5);
Aim 2) investigating the incorporation of dynamics over time into predictive models
(Chapter 6);
Aim 3) developing a novel method for non-invasive identification of ALF based on the
electronic nose (e-Nose) technology (Chapter 7).
The second part of the thesis has two aims:
Aim 1) investigating the impact of definitions on incidence, time to diagnosis, severity of
AKI, and mortality (Chapter 8);
Aim 2) assessing the predictive performance of alternative bio-markers (Chapter 9 and
10).
Chapter 11 presents a general discussion and a summary of the thesis.
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