Hepatol Int DOI 10.1007/s12072-015-9627-z
REVIEW ARTICLE
Pattern and profile of chronic liver disease in acute on chronic liver failure Zaigham Abbas1 • Lubna Shazi2
Received: 21 March 2014 / Accepted: 30 March 2015 Ó Asian Pacific Association for the Study of the Liver 2015
Abstract The etiology of the chronic liver disease (CLD) in patients with acute on chronic liver failure (ACLF) may vary from region to region. The major cause of underlying CLD is viral (hepatitis B and C) in the East, while it is alcohol related in the West and in some parts of the Indian subcontinent. Autoimmune liver disease and Wilson’s disease are the major underlying etiologies in the pediatric age group. The patients with CLD without cirrhosis should be included when defining ACLF. Non-alcoholic fatty liver disease related chronic liver insult in patients with known risk factors for progressive disease should be taken as a chronic liver disease in the setting of ACLF, whereas fatty liver with normal aminotransferases in low risk patients should not. The patients with CLD and previous decompensation should be excluded. Diagnosis of chronic liver disease in the setting of ACLF is made by history, physical examination and previously available or recent laboratory, endoscopic or radiological investigations. A liver biopsy through the transjugular route may help in cases where the presence of underlying CLD or its cause is not clear. The need of liver biopsy in ACLF should, however, be individualized. Standardization of liver biopsy assessment is essential for a uniform approach to the diagnosis and treatment of CLD and acute insult. Tools to measure liver stiffness may aid in identifying patients with advanced fibrosis. Studies are needed to validate the performance of these tests in the setting of ACLF.
Keywords Chronic liver disease Acute on chronic liver failure Chronic hepatitis Fibrosis Cirrhosis Fatty liver
Introduction Acute on chronic liver failure (ACLF) has been recognized as an entity different from acute decompensation of cirrhosis. However, there has been a debate between the East and the West on where to a draw a line between ACLF and acute decompensation [1, 2]. What are the factors that lead to ACLF instead of simple decompensation? Is it the different etiology, or different immune and cytokine response? Is it the number of organs failed or differences in the cut offs? There are many issues related to underlying chronic liver disease (CLD) as well. Does the CLD without cirrhosis need to be considered? Should nonalcoholic fatty liver be considered as chronic insult or not? Should presence of cirrhosis with prior decompensation and recovery, and a fresh acute insult leading to an ACLF like presentation be included in the definition or not? What methods should be employed for assessing CLD in ACLF; invasive or non-invasive? Recent consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) has addressed these issues [3]. We discuss this here with some details.
Etiology of CLD in ACLF & Zaigham Abbas [email protected]; [email protected] 1
Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
2
Liver Clinic Akber Centre, Karachi, Pakistan
The etiology of the CLD and the acute event leading to ACLF may vary from region to region. Diseases qualified as underlying CLD include compensated cirrhosis of any etiology, chronic hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis (NASH), cholestatic liver disease,
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and metabolic liver disease [1]. The major cause of underlying chronic liver disease is viral in the East while it is alcohol related in the West and in some parts of the Indian subcontinent. Hepatitis B and C related chronic liver disease is prevalent in the Asia Pacific region [4–44]. Patients with autoimmune liver disease, Wilson’s disease, and alcoholic hepatitis may present for the first time with ACLF [1]. The etiology of underlying chronic liver disease in ACLF in different studies has been mentioned in Table 1. It shows differences in etiologies in the East versus West. As there was no consensus on the definition of ACLF, some studies have included critically ill patients with liver cirrhosis who may not fulfil all the APASL criteria of ACLF. Autoimmune liver disease and Wilson’s disease are the major underlying etiologies in the pediatric age group [16, 18].
CLD without cirrhosis Diagnosis of CLD in ACLF is made on the basis of known history of chronic hepatitis or cirrhosis, signs of CLD, or with results of imaging or biopsy, indicating the existence of chronic liver insult. The term ‘‘acute on chronic’’ would be inferred as acute exacerbation of chronic liver damage by the acute insult regardless of the presence or absence of cirrhosis. Hence, by this description, patients with CLD along with lesser degree of fibrosis cannot be excluded. The degree of fibrosis remains heterogeneous in patients with the chronic insult and the same is true for the overall critical mass [45]. Fibrosis may be predominantly portal or centrilobular, depending on the etiology. Even in patients with stage IV disease, critical mass varies according to the parenchymal reserves. Stage IV fibrosis is not the end of the story as the degree of fibrosis may differ in the stage IV disease. The modified Laennec scoring system divides or subclassifies stage IV further into three stages based on the thickness of septa, making up six stages altogether [46, 47]. So the functional liver parenchymal mass varies within the stage IV and consequent progression of fibrosis from stage one to six. Moreover, ACLF is not equivalent to the acute decompensation of cirrhosis, which is the result of parenchymal extinction. Many ACLF patients present without the prior assessment of liver disease, and the current non-invasive methods to assess fibrosis have not been individually validated in the setting of ACLF. It is not possible to distinguish accurately patients with different degree of fibrosis at this point in time. The liver with any degree of fibrosis, with activated stellate cells, and infiltrated by the inflammatory cells, is expected to respond in a different way to the acute insult in comparison to the liver without inflammatory infiltrate. Elevated levels of multiple pro- and anti-inflammatory cytokines have been described in ACLF [48]. The response
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to the acute injury depends not only on the underlying liver disease, but also on the nature of the acute insult, immune response, and organ failure [49–51]. The dysregulated immune response in a diseased liver may be the reason that the model for end sage liver disease (MELD) and sepsisrelated organ failure assessment (SOFA) scores [52, 53] that are used for the assessment of the severity of organ failure do well in predicting mortality in ACLF [40].
Fatty liver Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive lipids in hepatocytes, in the absence of significant alcohol consumption or other potential secondary causes. Though the vast majority of patients with NAFLD have benign disease, a significant proportion of patients have associated inflammation in the liver leading to fibrosis and eventually cirrhosis. Would fatty liver with normal transaminases need to be considered as a chronic liver insult in the setting of ACLF? Fatty liver is not a normal liver. Liver lipotoxicity is associated with mitochondrial dysfunction in liver [54], and liver fat is also linked with metabolic complications of obesity [55]. Patients with the metabolic syndrome may have progressive liver disease, even with the apparent benign initial biopsy [56–58]. NAFLD is the leading cause of donor rejection in the living donor liver transplantation [59]. Experience from liver transplantation centres shows that steatosis [30 % in the donor liver is associated with a higher risk of primary non-function and graft initial poor function, as compared to grafts with no or\30 % steatosis [60]. Patients with metabolic syndrome and fatty liver, diabetics, male patients of age [45–50 years, as well as patients with obesity and dyslipidemia have the increased risk of fibrosis [61]. It is not always possible to exclude inflammation in NAFLD by liver biopsy. The inflammation and hepatocyte ballooning are unequally distributed in NAFLD and may be missed even in liver biopsy resulting in under-diagnosis in some patients [62]. Moreover, aminotransferases improve or normalize spontaneously over time, despite progression of fibrosis [63]. On the other hand, NAFLD in the absence of hepatocellular inflammation may not always be progressive [64] while NASH is a progressive chronic liver disease leading to advanced fibrosis and cirrhosis [65, 66].
CLD with pervious decompensation Patients with previous episodes of decompensation with jaundice, hepatic encephalopathy, and ascites comprise a mixed population of patients with previous ACLF that
Hepatol Int Table 1 Etiology of underlying chronic liver disease in acute on chronic liver failure (ACLF): East versus West Study ID
Country
Total
Viral
Alcohol
Alcohol with viral
Cryptogenic
Misc.
East Hamid et al. [4]
Pakistan
4
3 (75)
1 (25)
Choi et al. [5]
Korea
10
8 (80)
2 (20)
Du et al. [6]
China
650
524 (81)
Wagholikar et al. [7]
Singapore
9
7 (78)
Wai et al. [8]
Singapore
26
11 (42)
4 (15)
5 (19)
6 (24)
Acharya et al. [9]
India
42
28 (67)
7 (17)
4 (9)
3 (7)
Kumar et al. [10]
India
43
43 (100)
Krishna et al. [11]
India
121
42 (35)
17 (14)
44 (36)
18 (15)
5 (4)
44 (32)
14 (13) 6 (12)
8 (8) 1 (2)
80 (12)
Mahtab et al. [12]
Bangladesh
139
88 (63)
2 (1)
Duseja et al. [13] Rastogi et al. [14]
India India
102 50
13 (13) 33 (66)
62 (61) 10 (20)
El Sayed Zaki et al. [15]
Egypt
100
100 (100)
Lal et al. [16]
India
31
2 (6)
Garg et al. [17]
India
91
34 (38)
Jagadisan et al. [18]
India
17
1 (6)
46 (7) 2 (22)
5 (5)
29 (94) 31 (34)
Lin et al. [19]
Taiwan
54
39 (72)
Xia et al. [20]
China
857
602 (70)
56 (7)
Duan et al. [21]
China
100
91 (91)
6 (6)
171 (100)
22 (24)
4 (4)
6 (35)
10 (59)
7 (13)
8 (15) 149 (17)
50 (6) 4 (4)
Xu et al. [22]
China
171
Duseja et al. [23]
India
100
10 (10)
72 (72)
8 (8)
4 (4)
Jha et al. [24]
India
52
13 (25)
15 (29)
19 (36)
5 (10)
16 (29)
Carg et al. [25]
India
57
17 (29)
19 (33)
Kumar et al. [26]
Singapore
53
35 (66)
13 (25)
Khot et al. [27]
India
54
19 (35)
8 (15)
Dhiman et al. [28]
India
Agrawal et al. [29] Kedarisetty et al. [30]
India Asia Pacific
Shi et al. [31] Lee et al. [32]
50
6 (6)
5 (9) 5 (9)
15 (28)
12 (22)
7 (14)
6 (12)
3 (6)
29 (58)
5 (10)
106 1363
10 (9) 335 (25)
70 (66) 645 (47)
6 (6)
12 (11) 277 (20)
8 (8) 106 (8)
China
540
405 (75)
30 (6)
62 (11)
28 (5)
15 (3)
Korea
125
125 (100)
West Mitzner et al. [33]
Germany
13
3 (23)
7 (54)
Zauner et al. [34]
Austria
196
22 (11)
136 (70)
20 (10)
18 (9)
5 (4)
10 (7)
Wehler et al. [35]
Germany
143
20 (14)
108 (75)
Heemann et al. [36]
Germany
24
2 (8)
19 (79)
Wasmuth et al. [37]
Germany
Cholongitas et al. [38]
UK
Katoonizadeh et al. [39]
Belgium
70
5 (7)
61 (87)
Moreau et al. [40]
Europe
303
38 (13)
170 (56)
3 (23)
3 (13)
27
9 (33)
14 (52)
2 (7)
2 (8)
312
54 (17)
203 (65)
14 (5)
41 (13)
3 (4) 27 (9)
1 (2) 68 (22)
Angeli et al. [41]
Europe
489
67 (13)
292 (60)
46 (9)
84 (18)
Jalan et al. [42]
Europe
500
64 (13)
305 (61)
43 (8)
88 (18)
Silva et al. [43] Bajaj et al. [44]
Brazil USA
46 507
20 (44) 124 (25)
21 (46) 74 (15)
138 (27)
2 (4) 78 (15)
3 (6) 93 (18)
The values given are the numbers (%). Definition of ACLF variable. Term ‘‘cryptogenic’’ included non-alcoholic fatty liver disease in most studies
recovered, and those with decompensation due to ongoing downhill course [50]. These apparently compensated patients may have mild ascites on ultrasound, low albumin
and increased levels of international normalized ratio (INR), creatinine or bilirubin and elevated Child–Turcotte– Pugh (CTP) and MELD scores. Due to better nutritional
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support and the treatment with diuretics, they may appear compensated. As it is not always possible to distinguish between two groups; it would be more appropriate not to include patients with previous decompensation in the ACLF category at this point in time.
Diagnosis of CLD in ACLF Accurate and reliable assessment of underlying CLD in the setting of ACLF is important for the subsequent management of these patients. It would identify patients who would require intensive care and the treatment of underlying chronic insult in addition to the acute insult and its sequel. Diagnosis of chronic liver disease in the setting of ACLF is made by history, physical examination, and previously available or recent laboratory, endoscopic or radiological investigations [1]. The serology and nucleic acid testing are required to rule out viral etiology and tests to rule out metabolic and autoimmune diseases should be available. The presence of stigmata of liver disease on clinical examination, low platelets, evidence of synthetic dysfunction in previous reports, altered aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio in previous reports should prompt the diagnosis of the presence of CLD. A liver biopsy through the transjugular route may be of help when the presence of already underlying CLD and the cause of liver disease are not clear. The liver biopsy may highlight the etiology, stage of fibrosis and prognosis and outcome in patients with ACLF [14, 67]. In addition, transjugular access directly into the hepatic vein allows the hepatic venous pressure gradient (HVPG) to be measured. There is a risk of bleeding leading to hemobilia, hemoperitoneum, and hepatic hematoma in the setting of the deranged clotting profile. The need of liver biopsy in ACLF should, however, be individualized especially in alcoholic hepatitis, severe autoimmune hepatitis and flare of Wilson’s disease. Liver biopsy underestimates the degree of fibrosis and there is an inter-observer variability, particularly if the specimen size is \1.5 cm, or containing \10 portal triads [68, 69]. The diagnostic and prognostic value of transjugular liver biopsy is significantly improved when three individual, non-fragmented samples are submitted for analysis [70]. Standardization of liver biopsy assessment is essential for a uniform approach to the diagnosis and treatment of CLD and the acute insult. Multiple serial sections, two stained with hematoxylin and eosin (H&E) and one each with trichrome, periodic acid-Schiff (PAS), PAS-diestase, reticulin silver, and Perl’s iron stains should be evaluated [71]. These stains are sufficient for recording the necrosis, inflammation, fibrosis, and a number of
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common diseases affecting the liver. Additional stains such as Orcein to stain the rough endoplasmic reticulum of hepatitis B infected liver cells (ground glass cells), rubeanic acid for copper, and immunohistochemical stains can be used if indicated. A standardized system for reporting the acute insult and the chronicity should be adopted, for example, HAI by Ishak for activity and modified Laennec system for the presence of fibrosis and thickness of fibrous bands [46, 72]. There is a need to have reliable non-invasive tools to assess the severity of fibrosis in a previously undiagnosed CLD. Ultrasound and CT abdomen may pick up CLD. However, to assess the degree of fibrosis in an un-shrunken liver would require other radiological modalities. Transient elastography (fibroscan) is the best modality to detect fibrosis radiologically [73]. However, the liver tissue stiffness may also increase with hepatitis, steatosis, and inflammation present in the ACLF setting [74]. Other techniques include ultrasound based acoustic radiation force impulse (ARFI) [75, 76] and magnetic resonance elastography (MRE) [77, 78]. MRE has an edge over fibroscan and ARFI in its ability to assess liver as a whole instead of a limited field when using probes for fibroscan and ARFI. Moreover, it provides measurements even in the presence of obesity and ascites [79]. Studies are needed to validate the performance of these tests in the setting of ACLF. Serum based tests to assess fibrosis such as APRI (AST to platelet ratio index) [80], Fibrotest [81], and Hepascore [82] cannot be relied upon in the setting of acute inflammation of ACLF. Ultrasound is routinely used for the diagnosis of NAFLD. It picks up steatosis when[30 %. However, a mild degree of steatosis may be missed by ultrasound, even by CT scan. Magnetic resonance (MR) imaging, including MR spectroscopy has high sensitivity and specificity in quantifying steatosis [83]. However, it is expensive and not widely available. Noninvasive prediction tools may help in distinguishing NASH from simple NAFLD [83–85]. The NAFLD fibrosis score can be calculated from routine data, age, body mass index (BMI), AST/ALT ratio, platelet count, albumin, and blood glucose [86]. NAFLD fibrosis score [87] and enhanced liver fibrosis (ELF) panel may be used to predict NASH and fibrosis in patients with NAFLD [88, 89]. The score should be calculated from the previously available investigations as an acute insult may affect the score.
Conclusion The common diseases underlying CLD include alcohol, hepatitis B and hepatitis C. Autoimmune liver disease and Wilson’s disease are the major underlying etiologies in the pediatric age group. Chronic hepatitis and significant
Hepatol Int
fibrosis without cirrhosis should be taken as a chronic liver disease, if such a patient presents as ACLF. NAFLD-related chronic hepatic insult should be taken as a chronic liver disease in ACLF. Patients with known cirrhosis who have recovered from a previous decompensation and then decompensate again due to some acute insult, should be excluded from the ACLF. Diagnosis of CLD in the setting of ACLF is made by history, physical examination and previously available or recent laboratory, endoscopic or radiological investigations. A liver biopsy through the transjugular route is helpful where the presence of underlying CLD or its cause and the nature of the acute insult are not clear. Standardization of liver biopsy assessment is essential. Tools to measure liver stiffness may be of help in identifying patients with advanced fibrosis. Compliance with ethical requirements and Conflict of interest All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008 (5). The study protocol was approved by the National Liver Institute Institutional Review Board and the Ministry of Health IRB. Zaigham Abbas and Lubna Shazi declare that they have no conflict of interest. Informed consent Informed consent was obtained from all patients for being included in the study.
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REVIEW ARTICLE
Pattern and profile of chronic liver disease in acute on chronic liver failure Zaigham Abbas1 • Lubna Shazi2
Received: 21 March 2014 / Accepted: 30 March 2015 Ó Asian Pacific Association for the Study of the Liver 2015
Abstract The etiology of the chronic liver disease (CLD) in patients with acute on chronic liver failure (ACLF) may vary from region to region. The major cause of underlying CLD is viral (hepatitis B and C) in the East, while it is alcohol related in the West and in some parts of the Indian subcontinent. Autoimmune liver disease and Wilson’s disease are the major underlying etiologies in the pediatric age group. The patients with CLD without cirrhosis should be included when defining ACLF. Non-alcoholic fatty liver disease related chronic liver insult in patients with known risk factors for progressive disease should be taken as a chronic liver disease in the setting of ACLF, whereas fatty liver with normal aminotransferases in low risk patients should not. The patients with CLD and previous decompensation should be excluded. Diagnosis of chronic liver disease in the setting of ACLF is made by history, physical examination and previously available or recent laboratory, endoscopic or radiological investigations. A liver biopsy through the transjugular route may help in cases where the presence of underlying CLD or its cause is not clear. The need of liver biopsy in ACLF should, however, be individualized. Standardization of liver biopsy assessment is essential for a uniform approach to the diagnosis and treatment of CLD and acute insult. Tools to measure liver stiffness may aid in identifying patients with advanced fibrosis. Studies are needed to validate the performance of these tests in the setting of ACLF.
Keywords Chronic liver disease Acute on chronic liver failure Chronic hepatitis Fibrosis Cirrhosis Fatty liver
Introduction Acute on chronic liver failure (ACLF) has been recognized as an entity different from acute decompensation of cirrhosis. However, there has been a debate between the East and the West on where to a draw a line between ACLF and acute decompensation [1, 2]. What are the factors that lead to ACLF instead of simple decompensation? Is it the different etiology, or different immune and cytokine response? Is it the number of organs failed or differences in the cut offs? There are many issues related to underlying chronic liver disease (CLD) as well. Does the CLD without cirrhosis need to be considered? Should nonalcoholic fatty liver be considered as chronic insult or not? Should presence of cirrhosis with prior decompensation and recovery, and a fresh acute insult leading to an ACLF like presentation be included in the definition or not? What methods should be employed for assessing CLD in ACLF; invasive or non-invasive? Recent consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) has addressed these issues [3]. We discuss this here with some details.
Etiology of CLD in ACLF & Zaigham Abbas [email protected]; [email protected] 1
Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
2
Liver Clinic Akber Centre, Karachi, Pakistan
The etiology of the CLD and the acute event leading to ACLF may vary from region to region. Diseases qualified as underlying CLD include compensated cirrhosis of any etiology, chronic hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis (NASH), cholestatic liver disease,
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and metabolic liver disease [1]. The major cause of underlying chronic liver disease is viral in the East while it is alcohol related in the West and in some parts of the Indian subcontinent. Hepatitis B and C related chronic liver disease is prevalent in the Asia Pacific region [4–44]. Patients with autoimmune liver disease, Wilson’s disease, and alcoholic hepatitis may present for the first time with ACLF [1]. The etiology of underlying chronic liver disease in ACLF in different studies has been mentioned in Table 1. It shows differences in etiologies in the East versus West. As there was no consensus on the definition of ACLF, some studies have included critically ill patients with liver cirrhosis who may not fulfil all the APASL criteria of ACLF. Autoimmune liver disease and Wilson’s disease are the major underlying etiologies in the pediatric age group [16, 18].
CLD without cirrhosis Diagnosis of CLD in ACLF is made on the basis of known history of chronic hepatitis or cirrhosis, signs of CLD, or with results of imaging or biopsy, indicating the existence of chronic liver insult. The term ‘‘acute on chronic’’ would be inferred as acute exacerbation of chronic liver damage by the acute insult regardless of the presence or absence of cirrhosis. Hence, by this description, patients with CLD along with lesser degree of fibrosis cannot be excluded. The degree of fibrosis remains heterogeneous in patients with the chronic insult and the same is true for the overall critical mass [45]. Fibrosis may be predominantly portal or centrilobular, depending on the etiology. Even in patients with stage IV disease, critical mass varies according to the parenchymal reserves. Stage IV fibrosis is not the end of the story as the degree of fibrosis may differ in the stage IV disease. The modified Laennec scoring system divides or subclassifies stage IV further into three stages based on the thickness of septa, making up six stages altogether [46, 47]. So the functional liver parenchymal mass varies within the stage IV and consequent progression of fibrosis from stage one to six. Moreover, ACLF is not equivalent to the acute decompensation of cirrhosis, which is the result of parenchymal extinction. Many ACLF patients present without the prior assessment of liver disease, and the current non-invasive methods to assess fibrosis have not been individually validated in the setting of ACLF. It is not possible to distinguish accurately patients with different degree of fibrosis at this point in time. The liver with any degree of fibrosis, with activated stellate cells, and infiltrated by the inflammatory cells, is expected to respond in a different way to the acute insult in comparison to the liver without inflammatory infiltrate. Elevated levels of multiple pro- and anti-inflammatory cytokines have been described in ACLF [48]. The response
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to the acute injury depends not only on the underlying liver disease, but also on the nature of the acute insult, immune response, and organ failure [49–51]. The dysregulated immune response in a diseased liver may be the reason that the model for end sage liver disease (MELD) and sepsisrelated organ failure assessment (SOFA) scores [52, 53] that are used for the assessment of the severity of organ failure do well in predicting mortality in ACLF [40].
Fatty liver Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive lipids in hepatocytes, in the absence of significant alcohol consumption or other potential secondary causes. Though the vast majority of patients with NAFLD have benign disease, a significant proportion of patients have associated inflammation in the liver leading to fibrosis and eventually cirrhosis. Would fatty liver with normal transaminases need to be considered as a chronic liver insult in the setting of ACLF? Fatty liver is not a normal liver. Liver lipotoxicity is associated with mitochondrial dysfunction in liver [54], and liver fat is also linked with metabolic complications of obesity [55]. Patients with the metabolic syndrome may have progressive liver disease, even with the apparent benign initial biopsy [56–58]. NAFLD is the leading cause of donor rejection in the living donor liver transplantation [59]. Experience from liver transplantation centres shows that steatosis [30 % in the donor liver is associated with a higher risk of primary non-function and graft initial poor function, as compared to grafts with no or\30 % steatosis [60]. Patients with metabolic syndrome and fatty liver, diabetics, male patients of age [45–50 years, as well as patients with obesity and dyslipidemia have the increased risk of fibrosis [61]. It is not always possible to exclude inflammation in NAFLD by liver biopsy. The inflammation and hepatocyte ballooning are unequally distributed in NAFLD and may be missed even in liver biopsy resulting in under-diagnosis in some patients [62]. Moreover, aminotransferases improve or normalize spontaneously over time, despite progression of fibrosis [63]. On the other hand, NAFLD in the absence of hepatocellular inflammation may not always be progressive [64] while NASH is a progressive chronic liver disease leading to advanced fibrosis and cirrhosis [65, 66].
CLD with pervious decompensation Patients with previous episodes of decompensation with jaundice, hepatic encephalopathy, and ascites comprise a mixed population of patients with previous ACLF that
Hepatol Int Table 1 Etiology of underlying chronic liver disease in acute on chronic liver failure (ACLF): East versus West Study ID
Country
Total
Viral
Alcohol
Alcohol with viral
Cryptogenic
Misc.
East Hamid et al. [4]
Pakistan
4
3 (75)
1 (25)
Choi et al. [5]
Korea
10
8 (80)
2 (20)
Du et al. [6]
China
650
524 (81)
Wagholikar et al. [7]
Singapore
9
7 (78)
Wai et al. [8]
Singapore
26
11 (42)
4 (15)
5 (19)
6 (24)
Acharya et al. [9]
India
42
28 (67)
7 (17)
4 (9)
3 (7)
Kumar et al. [10]
India
43
43 (100)
Krishna et al. [11]
India
121
42 (35)
17 (14)
44 (36)
18 (15)
5 (4)
44 (32)
14 (13) 6 (12)
8 (8) 1 (2)
80 (12)
Mahtab et al. [12]
Bangladesh
139
88 (63)
2 (1)
Duseja et al. [13] Rastogi et al. [14]
India India
102 50
13 (13) 33 (66)
62 (61) 10 (20)
El Sayed Zaki et al. [15]
Egypt
100
100 (100)
Lal et al. [16]
India
31
2 (6)
Garg et al. [17]
India
91
34 (38)
Jagadisan et al. [18]
India
17
1 (6)
46 (7) 2 (22)
5 (5)
29 (94) 31 (34)
Lin et al. [19]
Taiwan
54
39 (72)
Xia et al. [20]
China
857
602 (70)
56 (7)
Duan et al. [21]
China
100
91 (91)
6 (6)
171 (100)
22 (24)
4 (4)
6 (35)
10 (59)
7 (13)
8 (15) 149 (17)
50 (6) 4 (4)
Xu et al. [22]
China
171
Duseja et al. [23]
India
100
10 (10)
72 (72)
8 (8)
4 (4)
Jha et al. [24]
India
52
13 (25)
15 (29)
19 (36)
5 (10)
16 (29)
Carg et al. [25]
India
57
17 (29)
19 (33)
Kumar et al. [26]
Singapore
53
35 (66)
13 (25)
Khot et al. [27]
India
54
19 (35)
8 (15)
Dhiman et al. [28]
India
Agrawal et al. [29] Kedarisetty et al. [30]
India Asia Pacific
Shi et al. [31] Lee et al. [32]
50
6 (6)
5 (9) 5 (9)
15 (28)
12 (22)
7 (14)
6 (12)
3 (6)
29 (58)
5 (10)
106 1363
10 (9) 335 (25)
70 (66) 645 (47)
6 (6)
12 (11) 277 (20)
8 (8) 106 (8)
China
540
405 (75)
30 (6)
62 (11)
28 (5)
15 (3)
Korea
125
125 (100)
West Mitzner et al. [33]
Germany
13
3 (23)
7 (54)
Zauner et al. [34]
Austria
196
22 (11)
136 (70)
20 (10)
18 (9)
5 (4)
10 (7)
Wehler et al. [35]
Germany
143
20 (14)
108 (75)
Heemann et al. [36]
Germany
24
2 (8)
19 (79)
Wasmuth et al. [37]
Germany
Cholongitas et al. [38]
UK
Katoonizadeh et al. [39]
Belgium
70
5 (7)
61 (87)
Moreau et al. [40]
Europe
303
38 (13)
170 (56)
3 (23)
3 (13)
27
9 (33)
14 (52)
2 (7)
2 (8)
312
54 (17)
203 (65)
14 (5)
41 (13)
3 (4) 27 (9)
1 (2) 68 (22)
Angeli et al. [41]
Europe
489
67 (13)
292 (60)
46 (9)
84 (18)
Jalan et al. [42]
Europe
500
64 (13)
305 (61)
43 (8)
88 (18)
Silva et al. [43] Bajaj et al. [44]
Brazil USA
46 507
20 (44) 124 (25)
21 (46) 74 (15)
138 (27)
2 (4) 78 (15)
3 (6) 93 (18)
The values given are the numbers (%). Definition of ACLF variable. Term ‘‘cryptogenic’’ included non-alcoholic fatty liver disease in most studies
recovered, and those with decompensation due to ongoing downhill course [50]. These apparently compensated patients may have mild ascites on ultrasound, low albumin
and increased levels of international normalized ratio (INR), creatinine or bilirubin and elevated Child–Turcotte– Pugh (CTP) and MELD scores. Due to better nutritional
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support and the treatment with diuretics, they may appear compensated. As it is not always possible to distinguish between two groups; it would be more appropriate not to include patients with previous decompensation in the ACLF category at this point in time.
Diagnosis of CLD in ACLF Accurate and reliable assessment of underlying CLD in the setting of ACLF is important for the subsequent management of these patients. It would identify patients who would require intensive care and the treatment of underlying chronic insult in addition to the acute insult and its sequel. Diagnosis of chronic liver disease in the setting of ACLF is made by history, physical examination, and previously available or recent laboratory, endoscopic or radiological investigations [1]. The serology and nucleic acid testing are required to rule out viral etiology and tests to rule out metabolic and autoimmune diseases should be available. The presence of stigmata of liver disease on clinical examination, low platelets, evidence of synthetic dysfunction in previous reports, altered aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio in previous reports should prompt the diagnosis of the presence of CLD. A liver biopsy through the transjugular route may be of help when the presence of already underlying CLD and the cause of liver disease are not clear. The liver biopsy may highlight the etiology, stage of fibrosis and prognosis and outcome in patients with ACLF [14, 67]. In addition, transjugular access directly into the hepatic vein allows the hepatic venous pressure gradient (HVPG) to be measured. There is a risk of bleeding leading to hemobilia, hemoperitoneum, and hepatic hematoma in the setting of the deranged clotting profile. The need of liver biopsy in ACLF should, however, be individualized especially in alcoholic hepatitis, severe autoimmune hepatitis and flare of Wilson’s disease. Liver biopsy underestimates the degree of fibrosis and there is an inter-observer variability, particularly if the specimen size is \1.5 cm, or containing \10 portal triads [68, 69]. The diagnostic and prognostic value of transjugular liver biopsy is significantly improved when three individual, non-fragmented samples are submitted for analysis [70]. Standardization of liver biopsy assessment is essential for a uniform approach to the diagnosis and treatment of CLD and the acute insult. Multiple serial sections, two stained with hematoxylin and eosin (H&E) and one each with trichrome, periodic acid-Schiff (PAS), PAS-diestase, reticulin silver, and Perl’s iron stains should be evaluated [71]. These stains are sufficient for recording the necrosis, inflammation, fibrosis, and a number of
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common diseases affecting the liver. Additional stains such as Orcein to stain the rough endoplasmic reticulum of hepatitis B infected liver cells (ground glass cells), rubeanic acid for copper, and immunohistochemical stains can be used if indicated. A standardized system for reporting the acute insult and the chronicity should be adopted, for example, HAI by Ishak for activity and modified Laennec system for the presence of fibrosis and thickness of fibrous bands [46, 72]. There is a need to have reliable non-invasive tools to assess the severity of fibrosis in a previously undiagnosed CLD. Ultrasound and CT abdomen may pick up CLD. However, to assess the degree of fibrosis in an un-shrunken liver would require other radiological modalities. Transient elastography (fibroscan) is the best modality to detect fibrosis radiologically [73]. However, the liver tissue stiffness may also increase with hepatitis, steatosis, and inflammation present in the ACLF setting [74]. Other techniques include ultrasound based acoustic radiation force impulse (ARFI) [75, 76] and magnetic resonance elastography (MRE) [77, 78]. MRE has an edge over fibroscan and ARFI in its ability to assess liver as a whole instead of a limited field when using probes for fibroscan and ARFI. Moreover, it provides measurements even in the presence of obesity and ascites [79]. Studies are needed to validate the performance of these tests in the setting of ACLF. Serum based tests to assess fibrosis such as APRI (AST to platelet ratio index) [80], Fibrotest [81], and Hepascore [82] cannot be relied upon in the setting of acute inflammation of ACLF. Ultrasound is routinely used for the diagnosis of NAFLD. It picks up steatosis when[30 %. However, a mild degree of steatosis may be missed by ultrasound, even by CT scan. Magnetic resonance (MR) imaging, including MR spectroscopy has high sensitivity and specificity in quantifying steatosis [83]. However, it is expensive and not widely available. Noninvasive prediction tools may help in distinguishing NASH from simple NAFLD [83–85]. The NAFLD fibrosis score can be calculated from routine data, age, body mass index (BMI), AST/ALT ratio, platelet count, albumin, and blood glucose [86]. NAFLD fibrosis score [87] and enhanced liver fibrosis (ELF) panel may be used to predict NASH and fibrosis in patients with NAFLD [88, 89]. The score should be calculated from the previously available investigations as an acute insult may affect the score.
Conclusion The common diseases underlying CLD include alcohol, hepatitis B and hepatitis C. Autoimmune liver disease and Wilson’s disease are the major underlying etiologies in the pediatric age group. Chronic hepatitis and significant
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fibrosis without cirrhosis should be taken as a chronic liver disease, if such a patient presents as ACLF. NAFLD-related chronic hepatic insult should be taken as a chronic liver disease in ACLF. Patients with known cirrhosis who have recovered from a previous decompensation and then decompensate again due to some acute insult, should be excluded from the ACLF. Diagnosis of CLD in the setting of ACLF is made by history, physical examination and previously available or recent laboratory, endoscopic or radiological investigations. A liver biopsy through the transjugular route is helpful where the presence of underlying CLD or its cause and the nature of the acute insult are not clear. Standardization of liver biopsy assessment is essential. Tools to measure liver stiffness may be of help in identifying patients with advanced fibrosis. Compliance with ethical requirements and Conflict of interest All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008 (5). The study protocol was approved by the National Liver Institute Institutional Review Board and the Ministry of Health IRB. Zaigham Abbas and Lubna Shazi declare that they have no conflict of interest. Informed consent Informed consent was obtained from all patients for being included in the study.
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