Non-invasive diagnosis of alcoholic liver disease

Table 1 Diagnosis of confirmed advanced fibrosis/cirrhosis (F3-4) (histology, elastography) by conventional clinical parameters (ultrasound, laboratory) from Salem Medical Center (n = 364)

Parameter	Pathologic	F0-2 elevated	F3-4 normal
Bilirubin	> 1.3 mg/dL	7.6%	58.3%
INR	> 1.27	1.2%	74.8%
Platelets	< 150 /nL	18.5%	49.6%
Spleen size	> 11.5 cm	6.4%	70.4%
Signs of liver cirrhosis	> 0	1.6%	59.1%
Bilirubin, INR, signs of liver cirrhosis	> 0	10.0%	43.5%
Bilirubin, INR, platelets, spleen size, signs of liver cirrhosis	> 0	27.7%	22.6%

The table shows typical findings of fibrosis/cirrhosis as indicated in the ultrasound (spleen size, signs of cirrhosis) or laboratory [bilirubin, international normalized ratio (INR) and platelets] in patients with no or low fibrosis stages (F0-2) vs advanced fibrosis stages (F3-4). In the last two rows, cirrhosis was considered if one of 3 or 5 parameters was pathologic. As an example, ca. 43% of F3-4 cirrhosis are not diagnosed by a combination of bilirubin, INR and ultrasound signs of liver cirrhosis.

Table 2 Fibrosis stages of alcoholic liver disease patients undergoing alcohol detoxication as determined by liver biopsy n (%)

Fibrosis stage	Histology	TE	All
F0	5	162	167 (45.9)
F1-2	46	36	82 (22.5)
F3	17	26	43 (11.8)
F4	21	51	72 (19.8)
Total	89	275	364

Preliminary data from Salem Medical Center (n = 364). TE: Transient elastography.

Table 3 Relative distribution of histological features in alcoholic liver disease patients

Kleiner score (range)	Considered elevated	Percentage
Kleiner steatosis 0-3	> 1	69.4%
Lobular inflammation 0-3	> 1	38.8%
Portal inflammation 0-1	> 0	15.3%
Ballooning 0-2	> 1	15.3%
Megamitochondria 0-1	> 0	1.6%
Mallory hyaline 0-1	> 0	25.9%
Classification steatohepatitis 0-2	> 0	75.3%

Preliminary data from Salem Medical Center (n = 89).

Table 4 Typical routine blood tests in alcoholic liver disease

Parameter	Pathologic	F0-2(<8 kPa)	F3-4(>8 kPA)	Mean F0-2	Mean F3-4
GOT (U/L)	> 50	56.9%	78.4%	89.5	135.4
GPT (U/L)	> 50	50.6%	48.6%	75.0	70.6
GGT (U/L)	> 60	69.4%	97.3%	238.8	792.8
AP (U/L)	> 130	9.0%	50.5%	90.2	152.0
Bilirubin total (mg/dL)	> 1.3	7.8%	43.2%	0.8	2.9
INR	> 1.27	0.8%	25.9%	1.2	1.1
Platelets (/nL)	< 150	17.5%	48.6%	222.5	172.0
Ferritin (ng/mL)	> 1000	15.6%	35.4%	524.7	830.7
Ferritin (ng/mL)	> 400	39.8%	60.4%	524.7	830.7
Triglycerides (mg/dL)	> 200	29.4%	25.7%	187.9	206.5
Cholesterine (mg/dL)	> 200	65.5%	52.8%	225.7	202.8
Albumin (g/dL)	< 3.8	4.3%	37.3%	5.4	5.2
Transferrin (g/A)	< 2	14.8%	38.6%	2.5	2.2
Transferrin saturation	> 45%	32.0%	45.9%	42.0	48.0
Hepatic steatosis (US)	> 1	70.9%	82.4%	1.9	2.2
Spleen size (cm)	> 11.5	7.5%	35.5%	9.6	11.1
Ascites	> 0	0.0%	20.7%	0.0	0.2
Signs of cirrhosis (US)	> 0	1.7%	43.9%	0.0	0.4
Liver stiffness (final)	> 8	0.0%	100.0%	4.8	32.7
CAP (dB/m)	> 300	42.2%	64.9%	287.0	308.3

The table shows percentage and means of pathologic routine blood tests in patients with alcoholic liver disease (ALD) (preliminary data from Salem Medical Center n = 275) solely characterized by non-invasive transient elastography (TE). US: Ultrasonography; CAP: Controlled attenuation parameter (Echosens); GGT: γ-glutamyl transpeptadase; GOT: Glutamic-oxal(o)acetic transaminase; GPT: Glutamate pyruvate transaminase; AFP: α-fetoprotein; AP: Alkaline phosphatase.

Table 5 Serum fibrosis markers in alcoholic liver disease

Serum marker	n	Outcome	Ref.
PIIINP	44	Correlation of PIIINP with fibrosis, but not inflammation or steatosis; PIIINP also positively correlated with ALP and GGT	Gabrielli et al[106], 1989
ApoA1	482	Correlation with fibrosis (r = -0.70; P ≤ 0.001)	Bedossa et al[107], 1989
PGA (GGT PT ApoA1) PT	624	AUROC not significant	Poynard et al[108], 1991
PIIINP, Laminin	44	PIIINP, PIIINP-Fab and laminin measured by RIA were 21 ± 19 μg/L, 90 ± 42 μg/L and 2.5 ± 0.8 U/mL in alcoholic cirrhosis	Lotterer et al[109], 1992
PIIINP Type I col	69	Correlation PIIINP and score of alcoholic hepatitis (r = 0.60, P ≤ 0.0001) Correlation type I collagen and fibrosis score (r = 0.34, P ≤ 0.001)	Trinchet et al[110], 1992
TIMP1, PIIINP	44	Correlation TIMP1 and fibrosis (r = 0.70, P < 0.001 AUROC 0.96 ± 0.03)	Li et al[111], 1994
CDT	74	Sensitivity of CDT for alcohol consumption 57% with 100% specificity	Seitz et al[112], 1995
HA, PIIINP	45	AUROC for PIIINP 0.867 ± 0.054	Pares et al[55], 1996
7S-IV col, TH-IV col, Laminin, TIMP	58	TH-IV concentration as best marker to distinguish ALD from non-ALD; good correlation between hepatic type V collagen and serum TH-IV, but not 7S-IV collagen; TIMP, may be useful in evaluating the degree of hepatic fibrosis	Tsutsumi et al[113], 1996
HA PT	160	Accuracy for cirrhosis diagnosis from 89.5% to 95%	Oberti et al[114], 1997
YKL-40	20	YKL-40 was significantly increased in patients with alcoholic cirrhosis (median, 523 μg/L; P < 0.001)	Johansen et al[115], 1997
YKL-40, HA, PGA, Tran index	146	Threshold of 330 μg/L gave sensitivity of 50.8% with specificity 88.5% Correlation HA and prothrombin index	Tran et al[116,117], 2000
HA	70	Significant correlation (P < 0.01) between HA and albumin, platelets and bilirubin, but not with ALT	Plevris et al[118], 2000
TPS	77	TPS correlated significantly with liver cell necrosis and Mallory's hyaline degeneration	González-Quintela et al[119], 2000
Laminin Type-IV col	80	Cut-off for Laminin 4.1 UI/mL gave 90% sensitivity, 77% specificity, cut-off for CIV 150 ng/mL gave 89% sensitivity 77% specificity	Castera et al[120], 2000
Type-VI col	61	CVI and CXIV as sensitive marker in fibrosis progression in alcoholics	Stickel et al[121], 2001
Type-XIV col	13
PT	243	Correlation PT and fibrosis score; r = -0.70, P < 0.0001	Croquet et al[122], 2002
YKL-40, PIIINP	370	Serum levels of YKL-40 and PIIINP are elevated in alcoholic patients; related to fibrosis	Nøjgaard et al[123], 2003
HA	87	Correlation HA and histological stage of ALD (r = 0.54, P < 0.0001); AUROC for HA and fibrosis 0.76	Stickel et al[124], 2003
ELF panel	64	AUROC 0.94 ± 0.056	Rosenberg et al[125], 2004

ALD: Alcoholic liver disease.

Table 6 Liver stiffness and fibrosis stages in alcoholic liver disease (biopsy proven studies)

Ref.	Patients (n)	Correlation	AUROCF4	Cut-offF4
Nahon et al[126], 2008	174	0.70, P < 0.0001	0.87	22.6
Nguyen-Khac et al[62], 2008	103	0.72, P < 0.014	0.92	19.5
Kim et al[127], 2009	45		0.97	25.8
Mueller et al[37], 2010	101	0.72; P < 0.001	0.92	11.5
Janssens et al[128], 2010	49		0.86	21.1

Table 7 Histological scores for alcoholic hepatitis

Ref.	Score	n	AUROC	Day survival	Histological parameters	INR	Bilirubin	Age	Albumin	Urea	Leuko	MELD	DF
Forrest et al[15], 2005	GAHS	241/195 (137)	0.65-0.71	28 and 84 d	Steatohepatitis	-	9	-	-	-	-	-	41
Mookerjee et al[129], 2011	ASH Grade	68	0.80	-	Fibrosis Cholestasis Cholangiolitis Steatosis Ballooning Steatosis	1.7	13.3	51	25	13.5	13.3	12.5	38
Affò et al[130], 2013	ASH score	121+205	0.74	90 d	Fibrosis Bilirubinostasis Megamitochondria PMN infiltration	1.6	9.7	49	-	-	-	18	-

ASH: Alcoholic steatohepatitis; PMN: Polymorphonuclear.

Table 8 Clinical scores and alcoholic hepatitis

Ref.	Score	n	AUROC			Parameters
			30 d	90 d	6 mo	INR	Bilirubin	Creatinin	Age	Leukocytes	Urea	Albumin	Bili decrease
Maddrey et al[14], 1978	DF	55				+	+
Dunn et al[131], 2005	MELD	73	0.83	0.86		+	+	+
Forrest et al[15], 2005	GAHS	241/195	0.81	0.78		+	+		+	+	+
Louvet et al[16], 2007	Lille model	295/115			0.89	+	+	+	+			+	+
Dominguez et al[132], 2008	ABIC	103/80				+	+	+	+