Accuracy of ultrasound to identify chronic liver disease

Table 1 Inclusion and exclusion criteria for studies

Inclusion criteria	Exclusion criteria
Evaluated diagnostic accuracy	Did not evaluate diagnostic accuracy
Quantitative results of diagnostic performance presented in a format that enabled a 2 × 2 contingency table to be extracted OR results presented as sensitivity, specificity and prevalence	2 × 2 contingency table could not be extracted from results of diagnostic performance OR sensitivity, specificity and prevalence results not presented
Index test of study was an ultrasound imaging technique	Index test included was not an ultrasound imaging technique OR included a non-ultrasound imaging technique as part of the index test
Studies were conducted prospectively	Studies were not conducted prospectively
The reference test for all subjects in the study was liver biopsy	The reference test for the study was not liver biopsy OR liver biopsy was not used for all subjects
The sample population described were adults at risk of chronic liver disease	The sample population described included children OR sample population included adults not at risk of chronic liver disease
	The study was published as a case study, review or editorial

Table 2 Quality assessment of diagnostic accuracy studies assessment items

Item	Question	Guidelines for assessment	Aspect of study assessed
1	Was the spectrum of patients representative of the patients who will receive the test in practice?	Patients who receive the test in clinical practice will be suspected of having chronic liver disease but not yet have decompensated cirrhosis	Generalisability
		Sample populations should fit this general characteristic. Samples may be a mixed population or may be restricted to one disease type if this is a common and clinically important disease, in this case alcohol abusers or viral hepatitis
		Score “yes” if clearly stated and meet the above definitions, “no” if the spectrum is clearly outside this definition and “unclear” if there is insufficient information
2	Were selection criteria clearly described?	Clear definitions of the inclusion and exclusion criteria should be included. “Yes” if clearly stated, “no” if not stated and ‘unclear” if only partially stated	Quality of reporting
3	Is the reference standard likely to correctly classify the target condition?	Liver biopsy must be used as the reference standard. “Yes” if biopsy used, “no” if not and “unclear’ if not stated	Presence of bias
4	Is the time period between reference standard and index test short enough to be reasonably sure that the target condition did not change between the two tests?	The time period must be no more than one month for all cases to avoid discrepancies between the index and reference test due to disease progression. The order in which the tests are done is not relevant. Score “yes” if one month or less, “no” if more than one month and “unclear” if not clearly stated	Presence of bias
5	Did the whole sample or a random selection of the sample, receive verification using a reference standard?	All patients should receive a biopsy unless some form of randomisation was used. Score “no” if some patients were excluded. Score “unclear” if this information is not reported by the study	Presence of bias
6	Did patients receive the same reference standard regardless of the index test result?	If it is clear all patients received a liver biopsy, score “yes”. If some received laparoscopy (or other test), score “no”. If it is not stated, score “unclear”	Presence of bias
7	Was the reference standard independent of the index test (i.e. the index test did not form part of the reference standard)?	Score ‘yes” if the index test did not form part of the reference test, “no” if it did and “unclear” if not stated or there is doubt	Presence of bias
8	Was the execution of the index test described in sufficient detail to permit replication of the test?	Studies should describe equipment and techniques in sufficient detail to enable replication. Ultrasound criteria for identifying fibrosis or cirrhosis must be clearly stated and be able to be replicated (e.g. clear and easily reproducible system for assessing grey scale appearances or Doppler measurements or indices)	Quality of reporting
		Score “yes” if the above is true, “no” if these details are not stated or if the technique described is not able to be replicated and “unclear” if an incomplete description is given
9	Was the execution of the reference standard described in sufficient detail to permit its replication?	A clear description of the biopsy technique sufficient to enable replication. Ideally this should include information about the needle technique used and the minimum size of the sample. A recognised staging system for fibrosis or a description with sufficient detail to enable replication must be provided	Quality of reporting
		Score “yes” if the above are true, “no” if no description of technique is given OR no staging system used and “unclear” if a partial description is given from which conclusions cannot be reached
10	Were the index test results interpreted without knowledge of the results of the index test?	Score “yes” if the ultrasound was performed and reported without knowledge of the biopsy. Score “no” if this is not the case and “unclear” if it is not stated	Presence of bias
11	Were the reference standard results interpreted without knowledge of the results of the reference test?	Score “yes” if the biopsy was performed and reported without knowledge of the ultrasound. Score “no” if this is not the case and “unclear” if it is not stated	Presence of bias
12	Were the same clinical data available when test results were interpreted as would be available when the test is used in practice?	Score “yes’ if pre-test clinical data was available for the ultrasound and biopsy. Score “no” if it was not available. Score “unclear” if it is not stated	Presence of bias
13	Were uninterpretable/intermediate results reported?	Score “yes” if all test results, including uninterpretable or indeterminate results, are accounted for. Score “no” if some data is missing and not explained or has been excluded from analysis. Score “unclear” if it is not clear whether all results have been included	Quality of reporting
14	Were withdrawals from the study explained?	A flow chart or matching numbers in a 2 × 2 table can help assess this item	Quality of reporting
		If it is clear what happened to all participants, score “yes”. If some patients are not accounted for, score “no”. Score “unclear” if interpretation is difficult

Table 3 Inter-rater reliability for quality assessment of diagnostic accuracy studies items

QUADAS item	Agreement (%)	κ
Representative spectrum?	90	0.4621
Selection criteria clear?	81	0.6321
Appropriate reference standard?	100	1.0001
Appropriate delay between tests?	100	1.0001
Partial verification avoided?	95	-2
Differential verification avoided?	95	-2
Incorporation avoided?	100	1.0001
Adequate index test description?	86	0.4681
Adequate reference test description?	76	-2
Index test blinded?	86	0.7041
Reference test blinded?	95	0.9011
Relevant clinical information available?	86	0.7121
Uninterpretable results reported?	29	0.022
Withdrawals explained?	33	0.033

¹Agreement significantly greater than chance (P < 0.05);

²A κ statistic could not be calculated because one reviewer responded "yes" for all studies on this item. QUADAS: Quality assessment of diagnostic accuracy studies.

Table 4 Characteristics of included studies

Author	Country	Sample	Males (%)	Mean age in years (range)	Prevalence of disease (%)	Aetiology (largest disease type)	Inclusion criteria	Exclusion criteria	Severity of disease
Joseph et al[17]	UK	50	NR	NR (NR)	62	Mixed (alcohol)	Abnormal LFT, clinical suspicion	NR	NR
Cioni et al[32]	Italy	117	77 (66)	47 (NR)	50	NR	Raised ALT	Decompensation, refused biopsy	Mild
Ladenheim et al [26]	USA	50	NR	NR (NR)	16	NR	NR	NR	NR
Ferral et al[35]	Mexico	70	28 (40)	49 (18-84)	46	Unclear	Abnormal LFT, non-specific clinically	Did not have biopsy (reasons not specified)	NR
Hultcrantz et al[28]	Sweden	83	47 (57)	41 (NR)	17	Mixed (“fatty” 54%)	Asymptomatic, raised AST/ALT	Signs of liver disease	Mild
Colli et al[29]	Italy	52	30 (58)	52 (22-65)	31	Viral	HCV, Child-Pugh class “A”	Decompensation, PHT	Mild
Gaiani et al[20]	Italy	212	128 (60)	49 (15-71)	22	Mixed (HCV 57%)	Raised AST, no prev. cirrhosis	Decompensation, PHT, previous history cirrhosis	Mild
Xu et al[22]	China	66	42 (64)	39 (NR)	36	Viral	HBV	NR	NR
Mathiesen et al[27]	Sweden	165	110 (67)	48 (22-77)	9	Mixed (“fatty” 40%)	Asymptomatic, raised AST/ALT	Decompensation	Mild
Colli et al[18]	Italy	300	234 (78)	49 (17-78)	36	Mixed (HCV 41%)	Asymptomatic, raised AST/ALT	Heart failure, atrial fibrillation	Mild
Nishiura et al[25]	Japan	103	60 (58)	51 (38-75)	21	Mixed (viral 88%)	Raised AST, no prev. cirrhosis	Decompensation, previous history cirrhosis	Mild
Colli et al[19]	Italy	176	96 (55)	54 (NR)	38	Viral	HCV, raised AST,	Decompensation, biopsy contra-indicated	Mild
							Child-Pugh “A”
Vigano et al[33]	Italy	108	55 (51)	53 (NR)	34	Viral	HCV	NR	NR
D’Onofrio et al[31]	Italy	105	73 (70)	47 (NR)	27	Viral	Asymptomatic viral hepatitis, raised AST/ALT	NR	Mild
Schneider et al[30]	Germany	119	66 (55)	45 (20-78)	14	Viral	HCV	NR	NR
Shen et al[16]	China	324	272 (84)	36 (18-60)	9	Viral	HCV,HBV, raised ALT	Decompensation, HIV,	Mild
								other causes of CLD
Liu et al[21]	Taiwan	503	271 (54)	52 (NR)	33	Viral	HCV	HBV, HIV, NASH, alcohol abuse, refused biopsy or contra-indicated	NR
Iliopoulos et al[23]	Greece	72	45 (63)	57 (NR)	39	Viral	Unclear	Unclear	NR
Paggi et al[24]	Italy	430	237 (55)	53 (25-71)	37	Viral	HCV	HBV, HIV, decompensation	Mild
Wang et al[39]	Taiwan	320	199 (62)	51 (NR)	33	Viral	HBV, HCV	HCC	NR
Gaia et al[34]	Italy	61	41 (67)	NR	36	Viral (62%)/NASH (38%)	NR	NR	NR

LFT: Liver function test; NR: Not reported; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; PHT: Portal hypertension; CLD: Chronic liver disease; HIV: Human immunodeficiency virus; NASH: Non-alcoholic steato-hepatitis; HCV: Hepatitis C virus; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma.

Table 5 Diagnostic accuracy of all ultrasound techniques

Study	Specific technique	Sensitivity	Specificity
Low frequency grey scale techniques
Schneider et al[30]	Spleen width	86.3	35.3
Schneider et al[30]	Spleen length	77.5	53.0
Joseph et al[17]	Liver parenchyma heterogeneity	77.0	89.0
Shen et al[16]	PV diameter	76.7	45.0
Iliopoulos et al[23]	Spleen volume	75.0	70.0
Shen et al[16]	Spleen length	60.0	75.0
Shen et al[16]	Splenic vein diameter	60.0	78.0
Hultcrantz et al[28]	Liver parenchyma echogenicity	43.0	42.0
Iliopoulos et al[23]	Liver parenchyma heterogeneity	43.0	77.0
Colli et al[18]	Caudate/Right lobe ratio	41.0	91.0
Mathiesen et al[27]	Liver parenchyma echogenicity	40.0	38.6
D’Onofrio et al[31]	Collateral vessels	39.0	84.0
D’Onofrio et al[31]	Caudate/Right lobe ratio	32.0	99.0
D’Onofrio et al[31]	Liver parenchyma heterogeneity	29.0	99.0
High frequency grey scale techniques
Ferral et al[35]	Surface	87.5	81.6
Colli et al[19]	Surface	60.0	92.0
Colli et al[18]	Surface	54.0	95.0
D’Onofrio et al[31]	Surface	54.0	78.0
Vigano et al[11]	Surface	51.0	90.0
Ladenheim et al[12]	Surface	12.5	88.0
Gaia et al[34]	Surface	63.0	86.0
Paggi et al[24]	Surface	73.0	90.0
Doppler techniques
Liu et al[21]	SA PI = 0.85	94.0	39
Liu et al[21]	SA PI = 1.20	88.0	82
Iliopoulos et al[23]	PV congestion index (PV cross-sectional area/PV Vtam)	86.0	66
Iliopoulos et al[23]	PV Diameter/PV Vmax	86.0	59.0
Iliopoulos et al[23]	PV Diameter/Vtam	86.0	68.0
Iliopoulos et al[23]	HA Vtam/PV Vtam	86.0	61.0
Iliopoulos et al[23]	PV Vmax	77.0	71.0
Schneider et al[30]	PV undulations	76.5	100.0
Colli et al[29]	HV pulsatility	75.0	78.0
Iliopoulos et al[23]	PV Vtam	75.0	71.0
Schneider et al[30]	PV Vmax	74.5	53.0
Iliopoulos et al[23]	HA RI	71.0	55.0
Cioni et al[32]	PV Vmax	66.0	98.0
Liu et al[21]	SA PI = 1.10	61.0	98.0
Iliopoulos et al[23]	PV blood flow (BF) (mL/min)	59.0	75.0
Colli et al[18]	HV pulsatility	57.0	76.0
Liu et al[21]	SA PI = 1.40	45.0	99.0
Iliopoulos et al[23]	Doppler perfusion index HA BF/(HA BF + PV BF)	43.0	91.0
Schneider et al[30]	HV pulsatility	31.4	47.1
Scoring systems
Nishiura et al[25]	Sequential score (high and low frequency techniques)	100.0	100.0
Xu et al[22]	4 parameter score (low frequency techniques)	87.8	97.6
Gaiani et al[20]	Score of low frequency and PV Vtam	82.2	79.9
Gaiani et al[20]	Score of 5-7 techniques (low frequency and PV Vtam)	78.7	80.6
D’Onofrio et al[31]	Any of 4 techniques (low frequency and liver surface)	68.0	68.0
D’Onofrio et al[31]	All of 4 techniques (low frequency and liver surface)	25.0	100.0
Wang et al[39]	Score of 4 parameters (low frequency techniques)	74.0	86.0

PV: Portal vein; SA: Splenic artery; PI: Pulsatility index; Vtam: Time averaged mean velocity; Vmax: Maximum velocity; HA: Hepatic artery; HV: Hepatic vein; RI: Resistive artery; BF: Blood flow.