Showing posts with label decompensated cirrhosis. Show all posts
Showing posts with label decompensated cirrhosis. Show all posts

Thursday, April 12, 2018

Liver Congress 2018 - ‘what you need to know in 5-minutes’ video clips each day from the conference

 ‘what you need to know in 5-minutes’

Hi folks, if you need help navigating the International Liver Congress, begin here: For Patients: The International Liver Congress 2018 . This page is a collection of links with conference updates and a list of websites you may be interested in visiting. As once a patient myself, exploring Practice Point was an easy way to review key data presented at the meeting.  Each day of the conference Practice Point uploads 5-minute video clips summarizing that day's hepatitis C presentations. However, you need to register, its free, check out the process below with highlights of today's clip. 

Link: Practice Point
Independent Conference Coverage from the 53rd Annual Congress of the European Association for the Study of the Liver (EASL)*
In this video series, Dr. Brown will present ‘what you need to know in 5‐minutes’ regarding today's presentations from The International Liver Congress EASL 2018 in Paris, France. These educational Clinical Clips will spotlight the latest advances in the prevention and treatment of hepatitis C through a series of daily, ‘what you need to know in 5-minutes’ videos each day from the conference. 

Clinical Clips Day One - April 12, 2018
Highlights: Harvoni® (Ledipasvir/Sofosbuvir) 8wks treatment vs 12wks in black treatment-naïve genotype 1 patients.

HCV genotype 3 using 8wks of Epclusa® (Sofosbuvir/Velpatasvir) for patients on Opioid Substitution therapy.

Epclusa® (Sofosbuvir/Velpatasvir) plus ribavirin for HCV genotype 3 patients with cirrhosis, and finally HCV treatment for patients with decompensated cirrhosis.
Start here.....

Check Practice Point each day of the conference, April-12 - April 15.

For patients, navigating registration
Link - Click here to register
The good news, only areas marked with * are required. The process is self-explanatory, it goes like this.

Email *
Confirm Email *
Password * Confirm Password *
First Name *
Last Name *
Degree * If you do not have a medical degree type in "Other" when the next box appears, type in "Patient"
Select the category that best represents your specialty * Pick one, anyone.
Areas of Interest (Check all that apply) * Pick one, anyone.

Good luck

Tuesday, October 31, 2017

HCV treatment in patients with decompensated liver disease

CLD Updates
Clinical Liver Disease (CLD) is a digital educational resource published on behalf of the American Association for the Study of Liver Diseases (AASLD). CLD publishes easy to read reviews on relevant topics for clinicians diagnosing and managing patients with liver disease. Each article is accompanied by a podcast audio version, and a video interview with the author to help emphasize the key teaching points for a clinical audience.

Volume 10 Issue 4 Issue Publication: October 2017

HCV treatment in patients with decompensated liver disease
Authors Elizabeth C. Verna First Published: 31 October 2017Vol: 10 
Pages: 83–86DOI: 10.1002/cld.663
Full Text (HTML)
PDF (189.7KB)
PDF (189.7KB)
Watch a video presentation of this article

Controversies in hepatitis C therapy: Reactivation of hepatitis B virus
Authors Sarah R. Lieber, Michael W. Fried
First Published: 31 October 2017 Vol: 10, Pages: 87–92 DOI: 10.1002/cld.665

Sunday, March 19, 2017

Hepatitis C - New therapies safe and effective in patients with decompensated cirrhosis

AGA Reading Room
New HCV Tx Works Well for Severe Liver Disease
by Liz Highleyman
Contributing Writer, MedPage Today

New therapies safe and effective in patients with decompensated cirrhosis

Treatment using direct-acting antivirals (DAAs) produces good cure rates in chronic hepatitis C (HCV) patients with decompensated liver disease, offering new options for a group that often could not be treated with interferon-based therapy. Successful treatment can slow liver disease progression and may restore lost hepatic function.

Genotype 1 or 4 patients who are ineligible, unable, or unwilling to take ribavirin can use the DAAs alone and increase treatment duration to 24 weeks. Patients with prior sofosbuvir failure should both add ribavirin and extend therapy to 24 weeks....
Continue reading...

Monday, May 5, 2014

Magnetic resonance elastography in compensated and decompensated cirrhosis

Magnetic resonance elastography in compensated and decompensated cirrhosis
Non-invasive predictors identifying subjects with compensated liver disease at highest risk for transitioning to a decompensated state are lacking. We hypothesized that liver shear stiffness as measured by magnetic resonance elastography is an important non-invasive predictor of hepatic decompensation. Dr. Sumeet Asrani discusses his article "Role of magnetic resonance elastography in compensated and decompensated liver disease"

What Is  - Magnetic resonance elastography (MRE)
 Researchers at Mayo Clinic have developed technology that uses sound waves to see if a patient's liver is harder than it should be — if it's developing fibrosis. It's called Magnetic Resonance Elastography (MRE), and it offers a noninvasive alternative to liver biopsy.


Wednesday, September 19, 2012

Proton pump inhibitors increased infection rate in decompensated cirrhosis patients

Proton pump inhibitors increased infection rate in decompensated cirrhosis patients

Bajaj JS. Aliment Pharmacol Ther. 2012;doi:10.1111/apt.12045.

Veterans with decompensated cirrhosis who started proton pump inhibitor therapy after decompensation were more likely than nonusers to develop serious infections in a recent study.

Researchers evaluated data from 1,268 US veterans who began proton pump inhibitor (PPI) use for decompensated cirrhosis between 2001 and 2009, along with 1,268 matched controls who did not use PPI. A parallel analysis was conducted of patients using H2 receptor antagonists (H2RA) (n=199) and matched controls (n=199). Incidence of serious infections requiring hospitalization, including skin, lower respiratory, urinary and kidney infections, along with Clostridium difficile, infectious gastroenteritis, sepsis and bactremia, was recorded.

Serious infections occurred in 25.3% of PPI users, with an incidence rate of 675 per 1,000 person-years. No association was found between PPI use and serious infection incidence rate (crude propensity-matched HR=1.08; 95% CI, 0.90-1.31), but infections related to acid suppression tended to occur more frequently in this group than among nonusers (crude HR=1.22; 95% CI, 0.97-1.52). Potential confounders, including age, race/ethnicity and concomitant medication, were similarly distributed between the two groups, but PPI users were more likely to have five or more comorbidities (41.2% of patients vs. 32.1% of nonusers).

Accounting for time-varying PPI use, serious infections were found to develop more quickly among PPI users than nonusers (adjusted HR=1.66; 95% CI, 1.31-2.12). Serious infections related to acid suppression also developed more quickly among PPI users (adjusted HR=1.75; 95% CI, 1.32-2.34), and comprised a larger number of all infections (75%) than among nonusers (64%).

Among H2RA users, 25.9% experienced serious infections, with 17.7% of patients developing infections related to acid suppression. Adjusted HRs were 1.59 for serious infection (95% CI, 0.80-3.18) and 0.92 for infections related to acid suppression (95% CI, 0.31-2.73) compared with nonusers. Neither result was statistically significant.

“Veterans with decompensated cirrhosis who were started on PPI therapy after decompensation had a significantly higher risk of developing serious infections compared with those who were not initiated on gastric acid suppression,” the researchers concluded. “As patients with decompensated cirrhosis remain at a high risk of serious infections, clinicians should reevaluate the reason for prescribing PPI and, wherever possible, replace their acid suppressive needs with H2RAs.”

Thursday, May 17, 2012

Neuropsychological dysfunction in cirrhosis and chronic hepatitis C

From Journal of Viral Hepatitis

Neuropsychological Tools in HepatologyA Survival Guide for the Clinician
S. Montagnese; S. Schiff; M. De Rui; M. M. E. Crossey; P. Amodio; S. D. Taylor-Robinson

Abstract and Introduction

Neuropsychological assessment has three main applications in clinical hepatology: (i) to detect, grade and monitor liver failure-related cognitive alterations in end-stage liver disease (hepatic encephalopathy), (ii) to substantiate complaints of attention or concentration difficulties in patients with non-cirrhotic chronic hepatitis C viral infection, and (iii) to screen patients who are being considered for liver transplantation for early signs of dementia. However, there is limited agreement on how cognitive assessment should be conducted in these patients, and how results should be interpreted and used to implement clinical decisions. In this review, we summarize the available literature on neuropsychological dysfunction in patients with cirrhosis and with chronic hepatitis C viral infection and provide some guidance on how to utilize neuropsychological assessment in practice.

Patients with end-stage liver disease have long been known to exhibit cognitive deficits in a variety of forms, which have been termed hepatic encephalopathy (HE). This spectrum ranges from minimal impairment, only detected on neuropsychological assessment (so called 'minimal hepatic encephalopathy' [MHE] – formerly labelled 'subclinical'),[1,2] through to overt hepatic encephalopathy (OHE), which can manifest as mild confusion and behavioural change through to deep coma.[3,4] More recently, it has become apparent that patients with chronic hepatitis C virus (HCV) infection complain of a variety of neuropsychiatric sequela including confusion ('brain fog'), anxiety and depression, in the absence of significant liver disease.[5] Most studies on these issues have been performed by hepatologists who have acted as amateur psychologists. In this review, we discuss some of the pitfalls of neuropsychological assessment and put the published studies on HE and non-cirrhotic chronic HCV infection into context.

Neuropsychological Assessment

The human mind produces an enormous set of complex behaviours. These events represent the net result of what cognitive psychologists refer to as mental operations and, as a whole, make up an individual's cognitive ability. This can be separated into domains, such as language, memory and attention (Appendix 1), and each domain can be assessed by specific neuropsychological tests.
Many conditions, including liver disease, impinge on the brain and on the patients' capacity to perform mental operations, thus on their cognitive ability. Neuropsychological assessment is the diagnostic process aimed at measuring an individual's cognitive ability by means of specific neuropsychological tests.[6] Neuropsychological evaluation is not based on the patient's history or complaints, or on his/her carer's observations, but relies on direct assessment of the patient's performance. Neuropsychological diagnosis is based on the systematic exploration of cognitive performance, with a view to defining mental functioning in patients with potential neurological or psychiatric illnesses.

In general, neuropsychological evaluation aims at defining impairment in aspects of cognition (i.e. memory, attention, language, executive function, etc.), which are thought to be sensitive to certain pathologies, and thus to be reliable indicators of their presence or absence. In this context, the scores obtained by a patient in a set of neuropsychological tests define the neuropsychological profile of the patient. The concept of neuropsychological profiling is an important one because, despite inter-individual differences (vide infra), a neuropsychological profile can, to some extent, 'define' a disease. For example, in individuals with suspected cerebro-vascular or Alzheimer-type mild cognitive impairment, isolated memory deficits on neuropsychological testing would support the diagnostic hypothesis.

Neuropsychological assessment requires meticulous attention to confounding variables. For example, physical pain may easily distract the patient from test instructions and test performance. As a consequence, the patient may be wrongly qualified as having attention or concentration deficits. Other variables that often confound neuropsychological assessment are mood (such as anxiety or depression) and sleep-wake disturbances. In addition, the evaluation of cognitive function needs to take into account socio-biological variables, such as age, sex, level of education and occupation, which are all known to affect performance. In recent years, considerable interest has arisen in the novel concept of cognitive reserve, or the degree of neuroprotection that derives from chronic enhancement of mental, social and physical activity.[7] Cognitive reserve can heavily impinge on performance in one or more cognitive domains. For example, professional sportspeople have been shown to have above average skills in certain cognitive domains, in relation to the type of sport practiced and the level of expertise.[8] Along the same lines, a London taxi-driver, who has learnt the geography of a big city almost by heart, may perform well on tests involving spatial attention abilities, despite a progressive disease that is impinging on his cognitive ability, including spatial attention. The same applies to accountants being tested on calculus and so on and so forth. This is because when an individual is tested, his/her baseline, premorbid performance is generally unknown. In addition, neuropsychological tests are scored in relation to reference, normative data obtained from large, supposedly healthy groups, stratified by country of origin or ethnicity, sex, age and level of education. Variables which make up the cognitive reserve, such as occupation and hobbies, are virtually impossible to account for in any meaningful way. Of importance to the hepatologist, the impact of cognitive reserve on both specific neuropsychological functions[9] and activities of daily living (i.e. driving)[10] has been documented also in patients with cirrhosis.

It is therefore obvious that to obtain clinically meaningful results, a neuropsychological assessment needs to be performed in a systematic fashion by adequately trained, experienced personnel.

Neuropsychological Assessment in Hepatology
In routine hepatological practice, neuropsychological assessment has different aims:
  • To detect, grade and monitor liver failure-related cognitive alterations (HE).
  • To substantiate complaints of 'brain fog' or 'concentration difficulties' in patients with HCV infection. In these patients, it has also been used to monitor treatment-related cognitive alterations (i.e. the side effects of interferon).
  • To screen individuals undergoing a transplant work-up for early signs of neuropsychiatric impairment (i.e. early dementia).
Hepatic Encephalopathy
HE is a reversible neuropsychiatric syndrome, which occurs in patients with cirrhosis and/or significant portal-systemic shunting.[3] HE manifests as a spectrum of change, which may or may not be clinically apparent. The neuropsychiatric changes detected in patients with cirrhosis by clinical examination are collectively termed OHE. The patient typically appears 'slow', somnolent, and sometimes euphoric, while in other instances obviously confused and disorientated. An involuntary jerking of the outstretched hands (flapping tremor) can be detected. The diagnosis can be difficult, especially in mild forms, thus a history obtained from a family member is valuable.[11] The detection of an obvious precipitating factor (i.e. infection or dehydration) can also help. It is important to notice how patients with cirrhosis are prone to the development of metabolic encephalopathies other than HE, such as those related to hyponatremia, hypoglycaemia and nutritional deficits, which should be ruled out.
The term MHE is used to describe the occurrence of neuropsychological and/or neurophysiological abnormalities (i.e. slowing of the electroencephalogram) in patients with cirrhosis who appear neuropsychiatrically normal on clinical examination.[1,12,13] The prevalence of MHE varies considerably, depending on the patient population studied and the tools utilized for the diagnosis. MHE predicts the subsequent occurrence of OHE,[14] impinging on the patient's ability to perform complex tasks, such as driving,[10,15,16] and usually impairing quality of life.[17] Therefore, it is important to screen for, recognize and adequately treat this syndrome.

Neuropsychological Dysfunction in Hepatic Encephalopathy: The Underlying Theory
Over the years, several different neuropsychological tests have been utilized to describe the effect of HE on various cognitive domains, to 'quantify' OHE and to diagnose MHE.[1,18] A review of the literature between 1970 and 2004 retrieved over 80 different tests, often exploring more than one cognitive domain.[19] Still, the large majority explored attention, motor speed and executive function (Appendix 1); a smaller number explored memory and the remainder other cognitive domains.

Attention has a crucial role within the cognitive system,[20] and it impinges on other cognitive functions. It is common experience that if a person does not pay attention to something, he or she may not be able to remember it later on, which does not necessarily imply that memory is not functioning properly. In addition, attention is the net result of three separate sub-functions: vigilance, spatial attention and selective attention (Appendix 1). Vigilance has not been directly measured in patients with HE, but there are both clinical[21] and electrophysiological data[22] to suggest that it is affected.[23] Selective attention seems to be more compromised than spatial attention in these patients, possibly explaining why they may be easily distracted[24] and why there is an inability to cope with conflicting tasks, or tasks which require to 'switch' between different sets of information.[25] The simplest, paper-and-pencil switching test is Trail-making test B: the patient is asked to connect numbers and letters in alternating order (1-A-2-B-3-C-4-D…), thus continuously switching between the alphabetical and the numerical sequence. Trail-making test B has been widely used in patients with cirrhosis and has proven more sensitive in detecting HE-related cognitive changes than Trail-making test A,[26] where the patient is only asked to connect numbers from 1 to 25. This is in line with results obtained by computerized neuropsychological tests, which can be helpful in dissecting a complex task in its components, and measure the time taken to perform each of them.[23] However, the delay in reaction time also depends on the complexity of the task, being progressively more marked in simple reaction times (i.e. reaction to a visual stimulus by pressing a key), compared with choice reaction times (i.e. pressing different keys in response to different visual stimuli), compared with reverse selection choice reaction times (i.e. reaction/inhibition to different visual stimuli).[27] In agreement with this concept, and based on the profound delay observed in patients with cirrhosis on reverse selection choice tasks,[28] a computerized inhibition test was recently proposed for MHE screening.[29,30] Along similar lines, a motor delay which was proportional to the cognitive load/difficulty of the task was observed in a working memory test.[31]

Limited consensus or solid data exist on which neuropsychological tests should be used to diagnose MHE and/or to quantify mild OHE. The approaches utilized so far to address this problem can be criticized as they have been 'circular' (i.e. choosing neuropsychological tests to measure functions that have been shown to be abnormal in patients with HE by neuropsychological tests), 'statistical' (i.e. choosing tests that are more often abnormal in these patients) or 'comparative' (i.e. choosing tests that often agree/overlap with other, non-neuropsychological measures of HE, regardless of the absence of a gold standard). Despite these problems, a set of reasonable suggestions were first provided by an expert panel at the 11th World Congress of Gastroenterology in 1998, and published in 2001.[12] The experts suggested that the presence of MHE should be defined by either: (i) two abnormal tests of a set of four (Trail-making Tests A and B, Symbol Digit, Block Design), or (ii) an abnormal Psychometric Hepatic Encephalopathy Score (PHES), based on a battery including Trail-making Tests A and B, Digit Symbol, Serial Dotting and Line Tracing.[32,33] The first criterion was derived from a previous, substantially arbitrary definition of MHE as a condition in which two psychometric tests are abnormal;[34] no information was provided on the total number/type of tests to administer. The second criterion was more solid, as the PHES battery was derived using discriminant analysis, in a formal attempt to maximize the separation of patients with cirrhosis with no electroencephalographic abnormalities from normal subjects and from alcohol misusers with no liver disease.[32,33]

The experts of the 11th World Congress of Gastroenterology panel recommended the use of neuropsychology as an alternative to that of neurophysiology, and, where possible, the combination of both techniques.[12]

More recent guidelines were produced by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN), separately for neuropsychology[35] and neurophysiology.[36] The former endorsed either the use of PHES or that of a more comprehensive battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),[37] which had been used in studies of patients with end-stage liver disease on a transplant list.[38] However, there is limited experience with RBANS in hepatology; the battery is time-consuming and it seems to exceed the requirements for standard, routine HE assessment.

The ISHEN guidelines did not formally endorse any of the computerized tests utilized so far in patients with cirrhosis, which include the Posner Test,[24] the Scan Test,[31] the Inhibitory Control Test[29] and the Cognitive Drug Research battery.[39] These have generally been chosen based on known cognitive features of HE and cover psychomotor speed, selective attention, inhibition and working memory. However, their use has not yet become widespread, and available normative data are limited.

Neuropsychological Dysfunction in Hepatic Encephalopathy: Actual Practice
Two of the authors of this review, SM (hepatologist) and SS (neuropsychologist), run a joint clinic for the assessment of neuropsychiatric dysfunction in Internal Medicine at the University of Padova, Italy. Our experience is that real patients are generally more complex than those enrolled in trials and observational studies and that attribution of reported or detected neuropsychological abnormalities to liver disease may not necessarily be straightforward. A standard HE evaluation at the Padova clinic includes: (i) a doctor's review, clinical and neurological examination, (ii) a structured interview with the neuropsychologist, (iii) a comprehensive neuropsychological evaluation, including both paper-and-pencil and computerized tests, (iv) an electroencephalogram, (v) a full blood count, liver function tests, renal function and electrolytes, venous ammonia, vitamin B12 and thyroid function tests. The case reports in Figs 1 & 2 illustrate how even this may not be enough and a definitive diagnosis may require further laboratory tests, cerebral imaging and re-evaluation after treatment. While it is difficult to imagine that such a comprehensive system may be routinely implemented in busy clinics and district hospital wards, it is equally important to remember that inaccurate neuropsychological diagnoses may impinge on quality of life,[17] post-transplant neurological outcome[40] and even survival.

Click Image To Enlarge

Figure 1.
Example of neuropsychiatric evaluation in a patient with alcohol-related cirrhosis. PHES, Psychometric Hepatic Encephalopathy Score, CRP, C-reactive protein, EEG, electroencephalogram, MRI, magnetic resonance imaging.

Click Image To Enlarge

Figure 2.
Example of neuropsychiatric evaluation in a patient with hepatitis C virus-related cirrhosis. PHES, Psychometric Hepatic Encephalopathy Score, EEG, electroencephalogram, TIPS, transjugual intrahepatic portal-systemic shunt.

Hepatitis C Virus and the Brain
In recent years, there has been growing evidence that neuropsychological changes in patients with chronic HCV infection may occur long before the development of significant liver fibrosis/cirrhosis.[41] A considerable proportion of patients with HCV infection complain of 'brain fog', weakness, fatigue and difficulties concentrating.[5] These problems do not seem to relate to HCV genotype or HCV replication, and their exact pathophysiology remains unknown, although a number of potential mechanisms have been proposed.[42]

Neuropsychological Dysfunction in Hepatitis C Virus: The Underlying Theory
In 2001, Forton et al.[43] described the presence of cerebral metabolic abnormalities – elevated choline/creatine ratio – in the frontal white matter and basal ganglia of HCV-infected patients by use of proton magnetic resonance spectroscopy. These alterations were not detected in either healthy age-matched controls or in patients with hepatitis B.[43] The following year, the same group of authors showed significant impairment in concentration and working memory in 27 patients with HCV infection and active viral replication, compared with 20 controls and 16 anti-HCV antibody positive, but HCV RNA-negative patients.[44]

Since these seminal observations, a number of studies have been published on neuropsychological performance in patients with hepatitis C.[45–51] Unfortunately, these have often included (i) patients with cirrhosis, (ii) patients who had acquired the infection by previous intravenous drug misuse, (iii) patients who had co-infections, (iv) patients who had had treatment with interferon not long before the study, (v) patients who were on psychoactive medication, or (vi) patients who complained of significant fatigue, which may all impinge on cognitive performance. More importantly, neuropsychological examination was not necessarily conducted in a systematic way, with different studies testing different, often isolated cognitive functions, making the results even more heterogeneous. Finally, very stringent cut-off values for abnormality were utilized (i.e. 1.5 SD from the reference values), at least in some instances.[48] Nevertheless, impairment was reported in sustained attention, executive function, verbal learning, verbal recall, memory and working memory.[5] To date, only two studies have been completely negative. In the first, HCV-positive patients were selected amongst supposedly healthy individuals, screened for purposes of blood donation, although the medical provenance of all subjects in the study was not fully elicited;[51] in the second, they were children/teenagers, probably with a shorter interval between infection and cognitive assessment, compared with all other studies.[52]

Interestingly, limited research has been performed to compare the neuropsychological burden of HCV-related cirrhosis and that of cirrhosis of other aetiologies, although clinical experience does not suggest there are significant differences.

Therefore, while patients with HCV infection have fairly definite magnetic resonance spectroscopy alterations,[43,44,47,48] which are unlikely to be explained by previous drug misuse or HE, their neuropsychological profile remains poorly defined. This is certainly worthy of further investigation, and so are the complex interactions between neuropsychological impairment, disease perception, mood, fatigue, daily functioning and quality of life.[53] These aspects are likely to become key to treatment choices for HCV-infected patients in the near future.

Neuropsychological Dysfunction in Hepatitis C Virus: Actual Practice
The practical difficulties of neuropsychological evaluation in patients with hepatitis C are even greater than those described for HE, for two main reasons: (i) the neuropsychological profile of these patients is not defined, and there is no consensus on which tests should be used, (ii) these patients often have additional reasons for cognitive dysfunction, such as psychoactive treatment, co-infections, previous drug/alcohol misuse and even the innate impulsiveness that characterizes addictive personalities.[54,55] This trait can affect both the approach to and the performance on several tests.
Within this very complex setting, also attention to common confounders needs to be meticulous, as illustrated in Fig. 3.

Click Image To Enlarge

Figure 3.
Example of neuropsychiatric evaluation in a patient with chronic hepatitis C infection. PHES, Psychometric Hepatic Encephalopathy Score, Lp(a), lipoprotein(a), HDL/LDL, high/low-density lipoprotein, MRI, magnetic resonance imaging.

When patients with cirrhosis or with non-cirrhotic chronic hepatitis C infection present with cognitive disturbance, it is often difficult to establish a causal relationship between their liver disease and their neuropsychological problems. Alcohol-related cerebral damage, bacterial infection, malnutrition, anaemia, vitamin deficiencies and renal failure can all be present in these patients, together with unrelated diseases of high prevalence, such as hypothyroidism and vascular/degenerative dementia.
For these reasons, neuropsychological batteries should be chosen, which include: (i) specific tests for the liver disease-related cognitive alterations of interest, and (ii) tests aimed at excluding gross, unrelated cognitive damage. The latter are even more important for patients who are being considered for transplantation, as subsequent treatment with immunosuppressants, especially calcineurin inhibitors, may unmask or accelerate cerebro-vascular disease.[40] Thus, when we evaluate a patient with cirrhosis, the battery will need to cover attention, visual-constructive, visual-motor and motor abilities (like PHES). If the patient is older than 55 years or is on a transplant list, long-term memory and executive function should also be tested, as an abnormal performance on Digit Symbol or Trail-Making test B, which are part of PHES, is also observed in early dementia. Similarly, visual-constructive impairment is common to both HE and Alzheimer's type dementia. However, the latter is also characterized by disturbance in long-term memory and praxis (Appendix 1). The presence of risk factors for cerebro-vascular disease, such as systemic hypertension, diabetes and hypercholesterolaemia, should prompt even more accurate differential diagnosis, as cerebro-vascular disease is associated, like HE, with extra-pyramidal motor disturbance. Previous substance or alcohol misuse is associated with working memory, planning, inhibition and decision-making issues, which can be picked up not only on test results but also on the patient's approach to tests performance.[55] Therefore, while hepatologists require simple tools for routine neuropsychiatric screening of their patients,[56] accurate neuropsychiatric diagnosis often requires the interaction between hepatologists and neuropsychologists, meticulous history taking, laboratory tests, neurophysiology, brain imaging and re-evaluation over time. A consensus is required as to a practical approach for neuropsychological testing in both HE and in chronic HCV infection. While no consensus exists on simple tests to use in the clinic, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) have commissioned a joint working party on this subject. The results of the working party's report are awaited in the next year.

Friday, March 16, 2012

Bacterial resistance in cirrhotic patients: An emerging reality

Journal of Hepatology
Volume 56, Issue 4 , Pages 756-757, April 2012
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Bacterial resistance in cirrhotic patients: An emerging reality

Gastroenterology, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy
published online 09 January 2012.
See Article, pages 825–832

Bacterial infections are frequent and represent a relevant issue in cirrhotic patients. Susceptibility to bacterial infections is increased in cirrhotic patients for multiple reasons. These patients show immunological dysfunctions, due to the so called “immune paralysis”, and an impairment in the reticuloendothelial system function resulting in a reduced ability of the liver to contrast the bacterial load from the intestine [1]. Moreover, they are predisposed to an increase in the rate and severity of “gut bacterial translocation” (GBT), defined as the migration of viable microorganisms and microbial products from the gut to mesenteric lymph nodes and other extra intestinal sites. GBT appears to be related mainly to three pathophysiological mechanisms: intestinal bacterial overgrowth, due to decreased small bowel motility, increased intestinal permeability, proportional to the degree of portal hypertension, and impaired local and systemic immunity [2]. All these factors are particularly evident in decompensated patients and GBT is reported to occur in 30–40% of patients with ascites.

Infections are particularly harmful in advanced liver disease. 
Decompensated cirrhotic patients suffering from a bacterial infection are more prone to develop a systemic inflammatory response syndrome [3]. In fact, hepatic dysfunction brings to a decreased cytokine clearance capacity leading to a “storm of pro-inflammatory mediators” (interleukin-1, interleukin-6, tumor necrosis factor alpha), which causes the conversion of a response normally useful against bacteria into a damaging inflammation. This may induce an increased demand of acute-phase-reaction proteins and an “exhaustion” of the hepatocytes reserve function and further aggravation of the splanchnic vasodilatation [4], [5]. In cirrhotic patients sepsis may induce complications such as renal failure and hepatic encephalopathy. In addition, the accelerated deterioration of liver function may lead to the so called “acute on chronic liver failure”. Severe sepsis may also cause the development of “multiple organ failure” defined by at least two of the following: renal failure, acute lung injury or acute respiratory distress syndrome, coagulopathy, brain failure, sepsis-induced adrenal insufficiency and shock [6].

Bacterial infections and sepsis are one of the main causes of death in hospitalized patients with chronic liver disease and seem to increase the 1-year mortality also in those discharged after the resolution of the infectious episode [7].

According to the hypothesis that the main mechanism in the onset of infection is the GBT, the pathogens more frequently isolated in cirrhotic patients are Gram-negative ones. Gram-positive bacteria are also found mainly in nosocomial infections, due to the large number of diagnostic and therapeutic invasive procedures which are needed in hospitalized patient [8].

A relevant issue emerging in recent years is the change in the epidemiological pattern of infections observed in cirrhotic patients. In the course of their illness, cirrhotic patients are frequently in need of day hospital care, recurrent hospitalization, or admission in intensive care units. The classification of infections in Community Acquired (CA) and Nosocomial (NA) has been recently recognized to be inadequate in the general population, and the term Health Care Related (HCR) infections, has been introduced to define a new epidemiological category [9]. According to the proposal of Friedman and co-workers, an infection is defined HCR if the diagnosis is made within 48h of hospitalization in a patient with a recent contact with the Health Care system (i.e. when the patient has attended a hospital or a hemodialysis clinic, or has received intravenous chemotherapy during the 30days before infection; or was hospitalized for at least 2days, or had undergone surgery during the 3months before infection; or has resided in a nursing home or a long-term care facility) [9]. HCR infections are associated with an increased prevalence of antibiotic resistant bacteria, have a worse prognosis and need to be treated according to different guidelines [10]. Recent data underline the need to separately consider this epidemiological group also in cirrhotic patients [11].

Antibiotic resistance in cirrhotic patients has been initially feared due to the chronic use of quinolones in secondary prophylaxis for spontaneous bacterial peritonitis (SBP). However, it has been clarified that quinolones-resistant strains are still sensitive to third generation cephalosporins (recommended first line therapy for SBP) [8], [12]. A more relevant emerging problem in cirrhotic patients is the increased prevalence of multidrug resistant (MDR) bacteria, frequently isolated in the NA and HCR groups. The definition of MDR pathogen includes methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii, extended-spectrum beta-lactamases-producing Gram-negative strains (ESBL), and any bacterial isolate resistant to at least three classes of antimicrobial agents [13]. In our experience, consecutive positive isolates from cirrhotic patients admitted in our unit, which is a tertiary referral center, in the last year evidenced an increase in MDR pathogens mainly in HCR and NA infections (33% in CA, 50% in NA and 80% in HCR; p=0.0000) [14].

The more important types of infection in cirrhosis are urinary tract infections, SBP, pneumonia and spontaneous bacteraemia [3], [11], [15]. SBP is the most common infection in some series and represents one of the most studied infections because of the severe prognosis and high rate of recurrence [8]. The outcome of PBS has improved significantly over the past 30years thanks to an early diagnosis, and, especially, to the use of a more appropriate antibiotic therapy as suggested in current guidelines [16].

The paper of Ariza and co-workers [17] provides interesting data about the prevalence of third generation cephalosporin resistance (MR-Cef) in cirrhotic patients with a diagnosis of SBP. The study is retrospective and analyzes 246 consecutive episodes of culture-positive SBP occurring in 200 cirrhotic patients in a single Spanish center between 2001 and 2009. As the current guidelines suggest the use of third generation cephalosporins for the first line empirical treatment of SBP, the authors evaluated the appropriateness of this regimen and the predictors of failure. The impact on mortality was also investigated. Some studies have already drawn their attention on the reduced efficacy of this therapy in recent years [18], [19].

The rate of MR-Cef was low in the group with CA infections (7.1%), intermediate in the HCR (21.1%), and high in the NA (40.9%), confirming the link between bacterial resistance and the epidemiology of infections. Previous use of cephalosporins, upper gastrointestinal bleeding, nosocomial acquisition and diabetes were found to be independent predictors of MR-Cef. Furthermore, the authors found a close association between the days of contact with the health care system and the likelihood of MR-Cef. A further important message coming from the study of Ariza and co-workers is that, besides the other factors related to the host condition, an inadequate empirical treatment of the infection was an independent predictor of 30-day mortality.

Some shortcomings of the study need to be underlined. Due to the retrospective design, the therapy was not properly standardized in all patients; in particular, ceftriaxone was utilized at a dose of 1g/24h for 5–10days while the dosage recommended in guidelines is cefotaxime 4g/day [13], [20] corresponding to at least 2g/day of ceftriaxone. Therefore, some patients could have been undertreated, causing a recurrence of SBP with MR-Cef strains. It is also interesting to note that 39 patients, all in severe clinical conditions, based on the physician decision, received piperacillin–tazobactam or imipenem as first line empirical therapy, determining a sort of “violation of the clinical protocol”. All these patients were classified as suffering from an HCR or a NA infection and, in 36%, the cultures eventually resulted in MR-Cef strains. In the statistical evaluation, the authors had to face this bias by excluding some of these patients from the analysis of mortality.

This study underlines the need of prospective studies in cirrhotic patients with bacterial infections, taking care of the different epidemiological conditions of bacterial acquisition. Different antibiotic protocols need to be compared for their efficacy and costs in different patients’ settings to define, based on the evidence, which is the most appropriate empiric antibiotic therapy according to their risk factors. Therapeutic trials need also to be extended to culture-negative SBP which frequently occurs in cirrhotic patients, and to infections located at different sites. Patients with long and multiple contact with the healthcare system are at high risk of infections sustained by multi-drug resistant strains and a change in the policy for the first line empirical antibiotic therapies in these patients is warranted.
Conflict of interest 
The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

  1. Wasmuth HE, Kunz D, Yagmur E, Timmer-Stranghoner A, Vidacek D, Siewert E, et al. Patients with acute on chronic liver failure display ‘‘sepsis-like’’ immune paralysis. J Hepatol. 2005;42:195–201
  2. Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology. 2005;41:422–433
  3. Cazzaniga M, Dionigi E, Gobbo G, Fioretti A, Monti V, Salerno F. The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome. J Hepatol. 2009;51:475–482
  4. Trautwein C, Boker K, Manns MP. Hepatocyte and immune system: acute phase reaction as a contribution to early defence mechanism. Gut. 1994;35:1163–1166
  5. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448–454
  6. Gustot T, Durand F, Lebrec D, Vincent JL, Moreau R. Severe sepsis in cirrhosis. Hepatology. 2009;50:2022–2033
  7. Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology. 2010;139:1246–1256
  8. Fernández J, Navasa M, Gómez J, Colmenero J, Vila J, Arroyo V, et al. Bacterial infection in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology. 2002;35:140–148
  9. Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al. Health care associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med. 2002;137:791–797
  10. Venditti M, Falcone M, Corrao S, Licata G, Serra P Study Group of the Italian Society of Internal Medicine. Outcomes of patients hospitalized with community-acquired, health care-associated, and hospital acquired pneumonia. Ann Intern Med. 2009;150:19–26
  11. Merli M, Lucidi C, Giannelli V, Giusto M, Riggio O, Falcone M, et al. Cirrhotic patients are at risk for health care-associated bacterial infections. Clin Gastroenterol Hepatol. 2010;8:979–985
  12. Runyon BA. Changing flora of bacterial infections in patients with cirrhosis. Liver Int. 2010;30:1245–1246
  13. Falagas ME, Koletsi PK, Bliziotis IA. The diversity of definitions of multidrug-resistant (MDR) and pandrug-resistant (PDR) Acinetobacter baumannii and Pseudomonas aeruginosa. J Med Microbiol. 2006;55:1619–1629
  14. Lucidi C, Giannelli V, Giusto M, Ruffa A, Lattanzi B, Riggio O, et al. High prevalence of MDR infections in cirrhotic patients who have had contact with the health care system. Hepatology. 2011;54:1236A
  15. Fasolato S, Angeli P, Dallagnese L, Maresio G, Zola E, Mazza E, et al. Renal failure and bacterial infection in patients with cirrhosis: epidemiology and clinical features. Hepatology. 2007;45:223–229
  16. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. European Association for the Study of the Liver. J Hepatol 2010;53:397–417.
  17. Ariza X, Castellote J, Lora-Tamayo J, Girbau A, Salord S, Rota R, et al. Risk factors for resistance to ceftriaxone and its impact on mortality in community, healthcare and nosocomial spontaneous bacterial peritonitis. J Hepatol. 2012;56:825–832
  18. Angeloni S, Leboffe C, Parente A, Venditti M, Giordano A, Merli M, et al. Efficacy of current guidelines for the treatment of spontaneous bacterial peritonitis in the clinical practice. World J Gastroenterol. 2008;14:2757–2762
  19. Cheong HS, Kang C, Lee JA, Moon SY, Joung MK, Chung DR, et al. Clinical significance and outcome of nosocomial acquisition of spontaneous bacterial peritonitis in patients with liver cirrhosis. Clin Infect Dis. 2009;48:1230–1236
  20. Rimola A, García-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol. 2000;32:142–153
PII: S0168-8278(12)00004-9


Sunday, December 11, 2011

Advanced Liver Disease: What Every Hepatitis C Virus Treater Should Know

Advanced Liver Disease Volume 19 Issue 3 August/September 2011

Please click below to listen to podcast and view text.

Advanced Liver Disease: What Every Hepatitis C Virus Treater Should Know

Audio Will Include Moments Of Hesitation/Silence During Podcast.....

Patients with advanced fibrosis need to be regularly monitored for evidence of decompensated disease, and complications need to be aggressively managed.....

This article summarizes a presentation by Kenneth E. Sherman, MD, at the IAS–USA live continuing medical education course, Management of Hepatitis C Virus in the New Era, held in New York City in April 2011.

Saturday, July 30, 2011

Obesity Linked to Risk for Decompensation of Cirrhosis

From Medscape Medical News

Obesity Linked to Risk for Decompensation of Cirrhosis

Laurie Barclay, MD
Authors and Disclosures

July 29, 2011 — Obesity is an independent risk factor for clinical decompensation (CD) in patients with cirrhosis, according to the results of a prospective observational study from the Portal Hypertension Collaborative Group reported online June 26 and to appear in the August print issue of Hepatology.

"Given the prior evidence of the detrimental effects of obesity on chronic liver disease, we hypothesized that increased BMI [body mass index] may increase the risk of transition from compensated to decompensated cirrhosis," said second author Guadalupe Garcia-Tsao, professor of medicine at Yale University School of Medicine in New Haven, Connecticut, in a news release.

Although obesity was previously known to be associated with an aggressive course in patients with chronic viral hepatitis, its effect on patients with established cirrhosis has been undetermined. The investigators therefore assessed the effect of obesity in patients with compensated cirrhosis, in conjunction with that of other known risk factors, on the development of CD.
The study sample consisted of 161 patients with compensated cirrhosis in whom data on BMI were available and who were enrolled in a randomized trial of beta-blockers to prevent varices. At study enrollment, participants underwent laboratory testing and measurement of portal pressure with use of the hepatic venous pressure gradient (HVPG). Follow-up continued until development of CD, defined as ascites, hepatic encephalopathy, or variceal hemorrhage, or until September 2002. Median duration of follow-up was 59 months.

At enrollment, 29% of participants had a normal BMI, 40% were overweight, and 30% were obese. CD occurred in 48 (30%) of 161 patients during follow-up. Rate of CD increased with increasing BMI: 15% in those with a normal BMI, 31% in the overweight group, and 43% in the obese group (P = .011). The groups with an abnormal BMI had a significantly higher actuarial probability of the development of CD (P = .022).

BMI was an independent predictor of CD (hazard ratio, 1.06; 95% confidence interval, 1.01 - 1.12; P = .02), as were HVPG and albumin, in a multivariate model that included factors previously determined to predict CD (HVPG, albumin level, Mayo end-stage liver disease score), cause, and treatment group.

"Patients who are overweight or obese are at greater risk of accelerating the progression of cirrhosis," Dr. Garcia-Tsao said. "Weight reduction may improve patient outcomes in this high-risk population and studies addressing this specific issue are warranted."
Limitations of this study include the fact that the original trial was not performed with the objective of evaluating the impact of obesity on CD.

"[I]ncreased BMI is an independent predictor of clinical decompensation in patients with compensated cirrhosis of various etiologies, suggesting that obesity accelerates the progression of cirrhosis and that its correction could be a valuable nonpharmacological measure to improve prognosis in this patient population," the study authors conclude.

The National Institutes of Health and the Instituto de Salud Carlos III supported this study. The study authors have disclosed no relevant financial relationships.

Hepatology. 2011;54:555-561.

Wednesday, May 4, 2011

Viral hepatitis: progress and promise

Focus on: Viral Hepatitis

Viral hepatitis: progress and promise
Natalie J. Wood  About the author
Since January 2000 there have been more than 40,000 research articles published on the subject of viral hepatitis—basic, translational and clinical. Such investment has been well rewarded, with advances in our understanding of the mechanisms of disease and improved treatment options. As viral hepatitis remains a major global health problem, these advances are much needed. In recognition of the interest in this field, Nature Reviews Gastroenterology & Hepatology commissioned a special focus issue to highlight some of the real-life issues pertinent to the present and future treatment and management of viral hepatitis
See; Nature Publishing Group

Also From Nature

Managing patients with hepatitis-B-related or hepatitis-C-related decompensated cirrhosis

This activity has been planned and implemented in accordance with the essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of MedscapeCME and Nature Publishing Group.

Treating a patient with decompensated cirrhosis may seem paradoxical. Decompensated cirrhosis is often thought of as the final, static, irreversible end stage of a process that had heretofore been dynamic and reversible. Indeed, replacement of the entire liver with an allograft is often seen as the only viable option to effect a cure of the patient's liver disease. However, treatment options are available for patients with HCV-induced or HBV-induced decompensated cirrhosis......

See; Nature Publishing Group

 *free registration may be required

Thursday, April 7, 2011


EASL Session Title: Category 02b: Cirrhosis and its complications: Clinical aspects

Presentation Date: 31 MAR, 2011


M. Kuehne1*, J. Wiegand1, P. Pradat2, J. Moessner1, F. Zoulim2, C. Trepo2, H.L. Tillmann1,3

1Gastroenterology and Rheumatology, University of Leipzig, Leipzig, Germany, 2Department of Hepatogastroenterology, Hôtel Dieu Hospital University, Lyon, France, 3Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA. *

Background: The clinical course of alcoholic versus non-alcoholic liver cirrhosis has not been well described yet. However, hepatic decompensation may be differentiated either in consequences of fibrosis (i.e. jaundice, variceal bleeding) or in lack of function (i.e. ascites) resulting in variable morbidity and mortality. We therefore evaluated the pattern of decompensation in relation to the etiology of liver cirrhosis.

Patients and methods: 220 cirrhotic German patients hospitalized between 2002 and 2006 were retrospectively evaluated (cohort A). Results were confirmed in a second cohort of German and French patients (cohort B: n=217) and in an overall analysis. Hepatic decompensation was defined as presence of either ascites, jaundice, encephalopathy, variceal bleeding, hepatorenal syndrome, spontaneous bacterial peritonitis, or hepatocellular carcinoma.

Results: In cohort A and B, alcoholic cirrhosis was present in 76.4% and 73.7% of cases. 8.9% of cases were in Child status A, 30.2% status B, and 44.6% status C (p=n.s.).

Compared to non-alcoholic cirrhosis (cryptogen n=37, HCV n=30, HBV n=11, other n=31), alcoholics (n=328) were significantly younger (55.6y ± 11.5 vs. 62.4y ± 12.8, p=0.000), more often male (75.9% vs. 53.2%; p=0.000) and smokers (60.8% vs. 28.8%; p=0.000).

Alcoholics were significantly more frequently hospitalized for ascites (cohort A: 56.5% vs. 38.5%, p=0,023; cohort B 53.2% vs. 36.8%, p=0.042; total: 54.6% vs. 37.6%; p=0.002) and showed a higher incidence of spontaneous bacterial peritonitis (total: 8.9% vs. 2.8%; p=0.033) compared to non-alcoholics. Non-alcoholics presented with significantly higher rates of hepatocellular carcinoma (31.2% vs. 17.2%; p=0.002). There were no significant differences in jaundice, variceal bleeding, hepatorenal syndrome, or encephalopathy.

A subgroup analysis of alcoholic vs. viral hepatitis confirmed ascites as dominant decompensation in alcoholics (54.6% vs. 36.6%; p=0.03).

In alcoholic cirrhosis, survival did not differ between cases with or without ascites (p=0.957). However, it was significantly impaired once ascites occurred in non-alcoholic disease (p< 0.001).

Conclusions: Ascites is the leading initial pattern of decompensation in alcoholic cirrhosis whereas hepatocellular carcinoma dominates in non-alcoholics. Non-Alcoholics developing ascites show a poor survival.

Monday, March 14, 2011

The Rate of Decompensation In Cirrhosis;Alcoholic, Viral Hepatitis, Autoimmune liver disease

The Rate of Decompensation and Clinical Progression of Disease in People with Cirrhosis

K. M. Fleming; G. P. Aithal; T. R. Card; J. West
Authors and Disclosures
Posted: 03/01/2011; Alimentary Pharmacology & Therapeutics. 2010;32(11):1343-1350. © 2010 Blackwell Publishing

We lack population-based estimates of the rate of decompensation in people with compensated cirrhosis as well as estimates of the manner in which the disease progresses once identified.

To determine the rate of decompensation and clinical progression of disease in patients with cirrhosis based upon clinical symptoms recorded electronically in general practice data.
Methods Using Cox proportional hazards regression, we modelled the rate of decompensation for patients from the UK General Practice Research Database with a diagnosis of cirrhosis between 1987 and 2002. We determined the clinical progression in the first year following diagnosis and subsequently categorizing patients through time according to a simple clinical staging system agreed at the Baveno IV consensus conference.
The rate of decompensation in patients with compensated cirrhosis was found to be 11% overall. The rate of decompensation was higher in the first year (at 31% compared with 7.3% afterwards) and in patients with an alcoholic aetiology. Patients with compensated cirrhosis had a 1-year probability of proceeding directly to death of 7% compared with 20% in patients with decompensated cirrhosis.
Using data recorded in general practice records, it is possible to determine the rate of decompensation and the clinical progression of disease in people with cirrhosis.

The natural history of cirrhosis has long been of interest to gastroenterologists and hepatologists[1–7] as knowledge of the progression of the disease allows planning of management and development of effective strategies for the primary prevention of complications and is of obvious interest to patients who wish to understand their risk of death, distressing symptoms and time to referral for consideration for transplantation. While in recent years advances have been made in the management of portal hypertension[8] with a consequent apparent improvement in some outcomes,[9] we have surprisingly little information on the effect of these developments on the natural history of cirrhosis in a general population-based setting. The most commonly referenced studies have focused on those patients who are admitted to hospital. In addition, while scoring systems such as Child-Pugh, MELD, UKELD enable the ranking of patients at an individual level and near the end stage of disease, we cannot at present provide useful absolute estimates of the rate of decompensation, clinical progression or mortality to patients in the earlier stages of disease.

In a recent comprehensive systematic review of the natural history and prognostic indicators of survival in cirrhosis which included 118 pertinent publications,[10] the authors reported a wide range of estimates of survival and factors that predicted death, but many methodological difficulties were also described. Perhaps most saliently they provided for the first time 1-year outcome probabilities for cirrhosis according to the clinical stages of disease agreed at the Baveno IV consensus conference.[11] However, as their estimates were based on the experience in a sole hospital in Sicily in the late 1970s–early 1980s, they may not be widely generalizable. We therefore do not have contemporary estimates of the progression of disease in cirrhosis at a population level.

Increasingly people are being diagnosed with cirrhosis at earlier stages of the disease i.e. compensated rather than decompensated. We have consequently taken the opportunity presented by prospectively recorded electronic primary care data from the UK to determine the rate of decompensation and the progression of disease in patients with cirrhosis based upon the Baveno IV stage of disease criteria.

Description of GPRD
The General Practice Research Database (GPRD) is a longitudinal database consisting of anonymous computerized general practice records for over 13 million patients in the UK, including over 50 million patient-years of usable data. Practices are subjected to regular data quality checks and audits to maintain 95% inclusion of prescribing and morbidity events. Data contained within this database are recorded through direct entry during general practice appointments and following communication from secondary care. Data are coded based on both the Oxmis and Read medical coding dictionaries. The GPRD has previously been shown to be broadly representative of the population of the UK[12] of which it represents approximately a 4–6% sample. Approval for this study was given by the Scientific and Ethical Committee of the GPRD.

Study Population
We obtained all records of patients with a diagnostic code for any liver disease within the GPRD between June 1987 and April 2002. Patients aged 25 years or over were then selected based on the presence of a diagnostic or therapeutic code for cirrhosis, oesophageal varices and/or portal hypertension to represent a cohort of adult diagnosed cirrhosis. This age cut-off was designed to avoid including patients who may have had the onset of cirrhosis under the age of 18. Each patient was assigned a date of diagnosis of cirrhosis as the date of the first record of any of these codes.

We then categorized patients with cirrhosis through time following date of diagnosis according to the four stages of cirrhosis as agreed at the Baveno IV conference[11]–
stage 1, uncomplicated cirrhosis i.e. cirrhosis in the absence of both oesophageal varices and ascites;
stage 2, cirrhosis with oesophageal varices, but without ascites and without bleeding;
stage 3, cirrhosis with ascites, with or without oesophageal varices;
and stage 4, cirrhosis with GI bleeding, with or without ascites.
Stages 1 and 2 together correspond to compensated cirrhosis with stages 3 and 4 together corresponding to decompensated cirrhosis. Each patient was assigned up to four dates corresponding to the earliest recording of the symptoms representing each stage. To minimize the potential for misclassification of patients with decompensated cirrhosis as patients with compensated disease we additionally looked for the recording of one or more prescriptions for spironolactone as evidence of decompensation.

Death was defined using a combination of the patient's registration status within the GPRD and medical codes for death, with the earliest date of these being assigned as the date of death.

Presumed aetiology of cirrhosis was defined as alcoholic, viral hepatitis, autoimmune liver disease or metabolic liver disease as previously reported.[13] For the purposes of analyses, all cases not defined as alcoholic were classified as non-alcohol-related cirrhosis.

Statistical Analyses
Using Cox proportional hazards, we modelled the rate of decompensation in the group of patients with compensated disease. Subjects entered the analysis period at the date of earliest recorded code for stage 1 or 2 and exited at the earliest of date of earliest recorded code for stage 3 or 4, date of death, date of liver transplant, date of deregistration with their general practice or 30 April 2002, which was the last date of available data in this dataset. We examined the rate of decompensation for subjects with alcoholic cirrhosis and those with non-alcohol-related cirrhosis. Follow-up time was split at 1 year and we modelled the rate of decompensation during the first year after diagnosis and subsequent to that first year again stratifying by presumed aetiology.

We examined the probabilities of patients with cirrhosis progressing from an individual stage to a subsequent stage or death within 1 year and across the whole time period of their records with 95% confidence intervals being calculated assuming a binomial distribution. We again stratified the cohort into those with alcoholic cirrhosis and those with non-alcohol-related cirrhosis.

A total of 4537 patients were identified with cirrhosis. Table 1 shows selected clinical and demographic information about the study population: 56.1% entered the study cohort at stage 1, 12.8% at stage 2, 23.0% at stage 3 and 8.1% at stage 4. A total of 2307 (50.9%) of cirrhosis cases were classified as alcoholic cirrhosis with the remainder being assigned as non-alcohol-related cirrhosis for the purposes of the subsequent analyses.

Rate of Decompensation
Overall, the rate of decompensation for those patients with compensated disease was 11.8% per year adjusted for age and gender [95%CI (11.2%, 12.5%)]. This figure varied considerably both by length of follow-up and by presumed aetiology. A Kaplan–Meier survival curve showing the difference in rate of decompensation by presumed aetiology is shown in Figure 1.

Figure 1.

Kaplan–Meier survival estimates for decompensation in subjects with compensated alcoholic and non-alcohol-related cirrhosis.

During the first year after diagnosis, the rate of decompensation was 31.0% adjusted for age and gender [95%CI (28.8%, 33.4%)]; for those patients with a presumed aetiology of alcoholic cirrhosis, the rate of decompensation during the first year was 37.6% [95%CI (34.1%, 41.5%)] compared with 25.2% [95%CI (22.6%, 28.2%)] for those with non-alcohol-related cirrhosis.

Following the first year, the rate of decompensation did not vary much by presumed aetiology with a rate of 7.3% per year adjusted for age and gender [95%CI (6.5%, 8.2%)] for those with alcoholic cirrhosis compared with an adjusted rate of decompensation of 5.5% per year [95% CI (4.8%, 6.2%)] for those with non-alcohol-related cirrhosis.

Outcome probabilities in the first year are shown in Figure 2. Patients in stages 1 and 2 had a 1-year probability of proceeding directly to death of around 7%. The probability of progression to death within 1 year was highest for patients within stage 3, rather than stage 4 (at 20.1% and 18.2% respectively), although this difference was not statistically significant.

Figure 2.
Probabilities for progression within 1 year, all patients.

State progressions across the whole study period are shown in Figure 3 Of note is the high proportion of people in the early stages of disease i.e. patients with compensated cirrhosis, who progressed directly to death without the recording of other clinical symptoms of decompensation. These results support the categorization of stages 1 and 2 together as representing compensated disease and stages 3 and 4 together as representing decompensated disease.

Figure 3.
Probabilities for progression across whole record, all patients.

The probabilities of progressing both during the first year and state progressions subsequently for those with alcoholic cirrhosis and non-alcohol-related cirrhosis are shown in Table 2 and Table 3 respectively. Reading across the table shows the stage at which patients began their follow-up. The rows in the column represent the stage to which the patients directly progressed. For example, looking at the first column, we can see that alcoholics who began follow-up in stage 1 had a 64.6% chance of remaining in stage 1 during the first year, with 2.9% progressing directly to stage 2 (oesophageal varices), and so on. In the first year following diagnosis, patients with alcoholic cirrhosis had a slightly higher probability of progressing to another stage of cirrhosis than those with non-alcohol-related cirrhosis, but a lower probability of progressing directly to death. Across the whole study period, patients with a presumed aetiology of alcoholic cirrhosis were again more likely to progress to another later stage of cirrhosis than those with non-alcohol-related cirrhosis. The differences in progression directly to death were not so marked across the whole time period, rather less patients with alcoholic cirrhosis remained in their entry stage with the exception of patients in stage 3.

Using the clinical observations recorded in primary care records of people with cirrhosis, we have described the progression of disease as experienced by patients and as recorded by primary care physicians in the UK. Progression of disease is rapid with the rate of decompensation in patients with compensated cirrhosis being 11% per year, but is particularly rapid in the first year following diagnosis at 31% in this first year. We have used a relatively simple staging system, based on the presence or absence of symptoms rather than relying on laboratory tests, mimicking the Baveno IV consensus clinical staging system to classify patients with cirrhosis. The classification is useful in long-term planning of management of patients with cirrhosis. We have applied this classification to an ambulatory population from primary care to describe the natural history of this disease. For example, in those patients without recorded evidence of portal hypertension, i.e. those in stage 1 of disease, there was about a 11% probability of progressing to a more severe form of disease (development of ascites, varices or GI bleeding) within a year alongside a 7% likelihood of dying. In those patients with stage 2 disease, the chance of developing ascites or bleeding was approximately 24% in the following year alongside a 7% risk of death.

By virtue of the electronic primary care data from a broad sample of primary care physicians at our disposal, we have constructed a large, representative, population-based cohort of patients with cirrhosis. This cohort was identified reasonably recently (1987–2002) and therefore the results we have generated reflect the natural history of cirrhosis during this period. As this is a population-based cohort, it is unlikely to have been affected by the variation in referrals and follow-ups seen in cohorts selected from secondary care. We are confident based upon our own previous validation study (which showed the vast majority of patients with a recorded code for cirrhosis had available extra evidence from secondary care[13] that for the diagnosis of cirrhosis in general this coding within primary care is good. The additional clinical signs and symptoms of decompensation may not always be recorded as accurately, however, unless they are of obvious clinical relevance to the GP. Hence, ascites is probably symptomatic and hence likely to be moderate to large-volume, clinically significant ascites (rather than that only identified by ultrasound). We acknowledge that there may have been some misclassification between stages 1 and 2 as the recognition of development of oesophageal varices in the absence of bleeding depends on endoscopic surveillance which, for the period our data cover, was not necessarily uniform in the UK. We believe though that it is unlikely that much misclassification has occurred between the compensated and decompensated disease states, nor between stages 3 and 4 as events such as bleeding oesophageal varices are of such importance that they are highly unlikely to be inaccurately recorded.

For the purposes of predicting progression of disease and mortality, we were unable to calculate the typically used Child-Pugh classification[14,15] or the more recently derived model for end-stage liver disease (MELD)[16] as we had no measures of blood indices available. However, we argue that the strength of Baveno IV consensus clinical staging system is that it allows such a broad evaluation of the natural history of patients with cirrhosis without relying upon laboratory tests. In addition, unlike Child-Pugh and MELD scores which are of limited value in early stages of cirrhosis where specific laboratory tests are unaltered (e.g. Child-Pugh class A patients), the Baveno classification can be applied to both early stage disease and late stage disease. This not only allows us to describe disease progression, but also to do so in a way which is intelligible both to nonspecialist clinicians and to patients. Of course, the simplicity of the Baveno classification is also one of its weaknesses in that many other factors that are known to influence the progression of cirrhosis, such as the development of hepatocellular carcinoma, hepatic encephalopathy and nutritional status are not included within the criteria.

We have included both incident and prevalent cases of cirrhosis by design as there is clear evidence that cirrhosis, as with most chronic diseases, has a wide heterogeneity of presentation. The results of our study therefore reflect the real world of clinical practice within the general population, which is unlikely to be true of series collected from within secondary care centres with a particular interest in the disease. This may explain some of the discrepancies with previously reported data as discussed below.

In comparison with historical studies of the natural history of cirrhosis,[1–6,10] our work shows that even in the later stages of the 20th century, progression of disease is rapid. Following our replication of outcome model of D'Amico et al. [10] using the Baveno IV stage of disease system, we found both similarities and differences with their reported findings. We found a similar clear demarcation of risk of death between compensated disease (stage 1 and stage 2) and decompensated disease (stage 3 and 4), although the probability of death within 1 year we observed for stage 1 disease and stage 2 disease was substantially higher than they reported. In contrast, we did not find a difference in the rate of progression to death for those patients with ascites rather than bleeding oesophageal varices. The explanation for these disparities most likely lies in the differences in methodology and population selection we have used. In the current study, we have taken each individual's record and defined his/her progression of disease within 1 year, whereas D'Amico et al. appear to report outcome probability estimates, which were averaged risks from 10 years of follow-up. In addition, we have used a population-based approach to collection of cases rather than the single centre approach previously used. The great benefits of a population-based approach i.e. avoiding bias and improving generalizability need no rehearsal, but in this case, the potential for misclassification of minor degrees of decompensation consequent upon lack of direct access to cases may explain some of the difference in our results. It is likewise probable that much of the difference between our results is a consequence of the fact that the UK, with low levels of chronic viral hepatitis, has a different aetiological picture with respect to cirrhosis from that seen in Sicily (the setting from which the Baveno classification was derived). Finally, some of the difference may be due to the era of data collection. Our finding that ascites is as severe a marker of poor prognosis as bleeding fits with the prevailing view that since the late 1970s, widely available important improvements have been made in the management and outcomes of variceal bleeding[17] with improvements in the treatments for ascites broadly limited to the administration of antibiotics in cases of spontaneous bacterial peritonitis, which is a much less frequent complication than bleeding.

A recent paper from Denmark looking at only alcoholic cirrhosis has provided similarly greater estimates for the 1-year progression directly to death in patients with no reported complications of 10% and similar estimates for 1-year progression directly to death for patients with clinical symptoms of ascites and variceal bleeding.[18] There are no such comparable figures for patients with non-alcohol-related cirrhosis available in current published literature.

In summary, our study has described the disease progression following a diagnosis of cirrhosis in contemporary clinical practice using data recorded electronically in general practice. Our reproduction of the use of a simple, internationally recognized, Baveno IV consensus clinical staging system is practical, useful and relevant to patients with cirrhosis and clinicians in the UK and beyond (within the limits of the assumptions underpinning its design). Of particular interest is the overall rate of decompensation for all those with cirrhosis as a contemporary estimate of this has not been readily available. Clearly, further validation of the approach we have used to stage disease in other datasets will be of value.
We conclude that our results in conjunction with the previously observed increasing incidence of cirrhosis emphasize the growing threat of liver disease to public health.

Abstract and Introduction