EASL Clinical Practice Guidelines

Diagnosis of ALD

Histological features of ALD

The morphological spectrum of ALD encompasses four groups of elementary lesions: (a) steatosis with a predominant future of macro-vesicles, associated or not with a variable blend of macro- and micro-vesicles, (b) hepatocyte damage often described as ballooning, (c) an inflammatory infiltrate which predominates in the lobules, and (d), a variable degree of fibrosis and lobular distortion which may progress to cirrhosis. [124]. In a given individual, a single lesion or any other combination of the other elementary lesions may be found [[125], [126]].

The prevalence and distribution of histological lesions among heavy drinkers is not well known. In a large series of 1407 patients admitted for alcoholism or ALD undergoing a liver biopsy, 14% of patients had normal liver, 28% pure steatosis, 20% fibrosis (with or without steatosis), 8.5% alcoholic hepatitis, and 29% cirrhosis [107]. Further studies among asymptomatic heavy drinkers should be performed.

Among the histological lesions of ALD, macrovesicular steatosis is the earliest and most frequently seen pattern of alcohol-induced liver injury [127]. Whether simple steatosis is a benign condition or can progress to more severe forms of ALD is a matter of debate. Some studies suggest that steatosis should no longer be considered a benign condition since cirrhosis may occur after a median of 10.5 years in 10% of patients with a histological diagnosis of simple steatosis without evidence of fibrosis or alcoholic steatohepatitis [128]. Other studies also suggested that steatosis, a common finding in active drinkers, is associated with more rapid progression of fibrosis.

Alcoholic steatohepatitis is defined by the coexistence of steatosis, hepatocyte ballooning and an inflammatory infiltrate with polymorphonuclear neutrophils. The presence of Mallory–Denk's bodies, and mega-mitochondria, although not specific to alcoholic steatohepatitis, are often associated with the elementary lesions described above. However, the presence of these lesions in a patient with ALD suggests active drinking.

The development of fibrosis is a key event in ALD since it is a prerequisite for the progression to cirrhosis. Fibrosis progression varies according to the histological lesions of ALD [[128], [129], [130], [131], [99], [132]]. Alcoholic hepatitis, steatosis, and the extent of fibrosis are independent, predictive factors of fibrosis progression. Among those lesions, patients with ASH exhibited the highest risk of fibrosis progression leading to the development of cirrhosis in at least 40% of cases [[129], [130], [99], [133], [134], [135]]. The persistence of ASH over a long period may accelerate the progression of fibrosis [135]. The ultimate stage of fibrosis is micro-nodular cirrhosis, which may occasionally be mixed micronodular and macronodular [126]. The assessment of the degree of fibrosis should be performed using special techniques, such as trichromic or Sirus red staining. Reticulin staining is advisable to assess both the extent of fibrosis and lobular architecture. Although semi-quantitative methods such as the Metavir scale are encountered, they are not validated in the setting of ALD.

Histological diagnosis of ALD requires a liver biopsy. It can be done percutaneously in most patients and requires a transjugular approach in patients with a low platelet count and/or a prolonged prothrombin time. However, liver biopsy is an invasive procedure with significant morbidity. Therefore, it is not recommended for all patients with suspected ALD. The precise indications of liver biopsy are not well established in routine practice. However, it is indicated in patients with aggressive forms of ALD such as severe steatohepatitis requiring specific therapies (e.g. corticosteroids and/or pentoxiphylline) and in patients with other cofactors suspected of contributing to liver disease. In the setting of clinical trials, the assessment of liver histology by performing a liver biopsy is recommended. Importantly, the assessment of liver histology allows a better prediction of the patient's outcome. Thus, it allows the risk of long-term mortality prognosis of patients with ALD to be classified according to the severity of the histological lesions [136]. An increase in mortality of at least 50% is observed in patients with histological diagnosis of ASH or cirrhosis as compared to those with only alcoholic steatosis [137].

Clinical diagnosis of ALD

Most patients with moderate forms of ALD are asymptomatic and it can only be detected by appropriate screening methods. Some patients can show signs suggestive of harmful alcohol drinking such as bilateral parotid gland hypertrophy, muscle wasting, malnutrition, Dupuytren's sign, and signs of symmetric peripheral neuropathy. In patients with cirrhosis, most physical findings are not specific of the etiology. However, some signs such gynecomastia and extensive spider angiomas may be more frequently seen in those with alcohol as the main cause of liver disease.

The diagnosis of ALD is frequently suspected upon documentation of excess alcohol consumption >30 g/d and the presence of clinical and/or biological abnormalities suggestive of liver injury. However, screening of ALD is difficult as significant proportions of patients with histological features of ALD do not show any clinical symptoms. Routine blood tests such as mean corpuscular volume (MCV), gamma glutamyl transpeptidase (GGT), glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) can indicate early ALD whereas advanced ALD is suspected if there is decreased albumin, prolonged prothombin time, increased bilirubin level or thrombocytopenia.

Although no single laboratory marker definitely establishes chronic alcohol consumption, carbohydrate deficient transferrin (CDT) and GGT are the most frequently used markers to detect previous alcohol consumption [138]. Indeed, the sensitivity for detection of daily ethanol consumption >50 g of CDT (69%), and GGT (73%) are higher than those of AST (50%), ALT (35%), and MCV (52%) [139]. The specificity of CDT was 92%, compared with 75%, 82%, 86%, and 85% for GGT, AST, ALT, and MCV, respectively [139]. As the measurement of GGT is easy and inexpensive, it remains the most frequently used marker for early detection of chronic alcohol misuse [140]. GGT is usually higher in ALD patients compared with those who have other liver diseases. However, serum GGT activity loses its specificity for alcohol in more advanced liver disease because its activity is elevated in patients with extensive fibrosis regardless of the cause [[141], [142]]. More recently, it has been shown that serum GGT activity is influenced not only by the amount of alcohol consumed but also by body mass index (BMI) and sex [143].

Elevation of aspartate amino transferase (AST) may be observed in all forms of ALD with a sensitivity of 50% and a specificity of around 80%. AST levels are rarely above 300 IU/ml, while serum alanine aminotransferase (ALT) levels are commonly lower. The AST/ALT ratio typically is greater than 1 [[144], [145]], although this finding is neither specific nor sensitive and it has also been shown to be an indirect marker of advanced fibrosis [146].

Non-invasive tests to estimate liver fibrosis

Serum markers

Several new blood tests combining different biomarkers of fibrosis are now available. Although these tests were initially designed for patients with hepatitis C, some of them seem to be efficient in patients with ALD. However, different cut-offs may have to be considered when using such biomarkers for ALD instead of hepatitis C.

Aspartate aminotransferase (AST) to platelet ratio index (APRI) has been evaluated in heavy drinkers. A total of 1308 subjects from two studies of ALD were evaluated, with a liver biopsy available from 781 non-cirrhotic patients and a history of decompensation in 527 patients [147]. In 507 patients with biopsy-confirmed fibrosis, the sensitivity of APRI for significant fibrosis was 13.2% and the specificity was 77.6%. Twenty percent were misclassified. Thus, APRI may be of limited use in the diagnosis of fibrosis in many patients.

FibroTest® is a serum biomarker of fibrosis combining alpha-2-macroglobulin, haptoglobin, GGT, ApoA1, and bilirubin, corrected for age and sex [141]. It seems to have high diagnostic potential for the detection of significant fibrosis in patients with ALD. In a study of 221 consecutive patients with biopsy-proven ALD, the mean FibroTest® value ranged from 0.29 in those without fibrosis to 0.88 in those with cirrhosis and its AUROC for the diagnosis of cirrhosis was at 0.95 [148]. FibrometerA®, combining PT, alpha-2-macroglobulin, hyaluronic acid, and age has similar diagnostic accuracy in ALD [149]. In the validating step, the Fibrometer® AUROC curve was 0.892 in overall patients and 0.962 in patients with ALD. Hepascore® combines bilirubin, GGT, hyaluronic acid, alpha-2-macroglobulin, age, and sex. The diagnostic accuracies of Fibrotest®, Fibrometer®, and Hepascore® were compared in patients with ALD [136]. The diagnostic values of FibrometerA® and Hepascore® did not differ from that of FibroTest® for advanced fibrosis (AUROCs around 0.80) and cirrhosis (AUROCs around 0.90), and were significantly greater than those of non-patented biomarkers (APRI, Forns, FIB4). The combination of any of these tests was useless in improving diagnostic performance [136].

In addition to their diagnostic performance in the screening of fibrosis, non-invasive tests may be useful in predicting liver-related mortality as shown in a study of patients with ALD followed-up for more than 8 years, where survival was correlated with baseline non-invasive fibrosis score [136]. ELF®, a panel of sensitive automated immunoassays to detect matrix constituents and mediators of matrix remodeling in serum [150] may also predict clinical outcomes in patients with chronic liver disease on long term follow-up [151]. However, its utility has not been fully evaluated in large cohorts of alcoholic patients.

Transient elastography (Fibroscan®)

Liver stiffness measurement (LSM) has been demonstrated to be a reliable tool for assessing hepatic fibrosis in patients with ALD [[152], [153], [154], [155], [156], [157]]. In patients with ALD, liver stiffness correlates with the degree of fibrosis. In the studies that did not consider the presence of ASH as a potential confounding factor, the cut off values for F3 and F4 fibrosis were considerably higher as compared to patients with viral hepatitis. In this regard, several studies have shown that patients with alcoholic cirrhosis had significantly higher values of liver stiffness than patients with viral cirrhosis, suggesting that the etiology may strongly affect the amount of fibrosis at the same stage. However, a recent study indicated that coexisting ASH markedly increases LSM in patients with ALD independent of fibrosis stage [[152], [158]].

The existence of inflammation, cholestasis or liver congestion may interfere with LSM, independently of fibrosis [159]. Since all these conditions may occur during ALD, LSM should always be interpreted in the context of clinical, imaging and laboratory findings. A decision tree, taking into account those parameters has been proposed for the use of transient elastography in heavy drinkers [158]. Importantly, elevated liver stiffness values in patients with ALD and ASAT serum levels >100 U/L should be interpreted with caution because of the possibility of falsely elevated liver stiffness as a result of superimposed ASH [152]. In addition, alcohol consumption may also modify LSM as shown by the decrease in liver stiffness among abstainers and the increase in relapsers [[152], [160]].

Hepatic imaging techniques

Imaging techniques such as ultrasonography, MRI, and CT may allow the detection of fatty liver, help exclude other causes of chronic liver disease and contribute to the assessment of advanced liver disease and its complications independent of the etiology [161]. However, imaging studies do not have a role in establishing alcohol as the specific etiology of liver disease.

Steatosis may be screened using ultrasonography, CT, and MRI. Among those methods, ultrasound probably has the lowest sensitivity and specificity, especially when steatosis is below a threshold of 20–30%. MRI and MR spectroscopy are reliable tools for assessing the amount of steatosis but the standardization of sequence characteristics are not established and their cost and availability are limiting [[162], [163]].

In clinical practice, ultrasonography may be proposed in heavy drinkers as a screening procedure for steatosis [164]. Ultrasonography can also be useful in detecting signs of advanced stages of ALD such as liver dysmorphy, portal-systemic collaterals and splenomegaly.

Recommendations

Suggestions for future studies

  1. Longitudinal studies using non-invasive tools should evaluate disease progression both in persistent heavy drinkers and after abstinence.
  2. New histological scoring systems integrating steatosis, steatohepatitis, and fibrosis should be specifically developed for patients with ALD.
  3. Future studies are warranted to propose and validate diagnostic algorithm including liver biopsy and non-invasive tests.