Clinical Characteristics of Alcohol-Related Liver Disease in Albanian Patients: A Cross-Sectional Study

Abstract

Background/Objectives: Alcohol-related liver disease (ARLD) is a major cause of chronic liver disease, yet its clinical profile in Albania, a region with high HBV prevalence and rising alcohol consumption, remains poorly characterized. This study evaluates the clinical markers of advanced ARLD as noninvasive fibrosis indicators, acknowledging limitations in observational data and the need for validation in diverse populations. Methods: In this cross-sectional study, 200 patients with ARLD were classified as having mild or advanced disease based on clinical, biochemical, and imaging criteria. Associations between socioeconomic factors, nutritional status, and fibrosis markers with advanced ARLD were assessed using multivariate logistic regression, adjusted for age, sex, smoking status, and duration of alcohol use. Results: Lower Prognostic Nutritional Index (PNI) score was significantly associated with advanced ARLD (OR 0.95, 95% CI 0.91–0.99; p = 0.014), suggesting a potential role of nutritional status in disease progression. Higher APRI and FIB-4 scores were associated with an increased risk of advanced ARLD (APRI: OR 1.27, 95% CI 0.71–2.26; FIB-4: OR 1.10, 95% CI 0.81–1.51), though these associations did not reach statistical significance. Conclusions: This study provides a first clinical assessment of ARLD in Albania, highlighting the potential role of nutritional and fibrosis markers in risk stratification. While the study design limits definitive conclusions, our findings underscore the need for larger prospective studies to validate these associations and further investigate the influence of metabolic and socioeconomic factors on ARLD progression in Albania.

1. Introduction

Alcohol-related liver disease (ARLD) remains a major cause of chronic liver disease worldwide, contributing substantially to morbidity and mortality [1]. In Europe, alcohol consumption is estimated to account for approximately 40% of premature liver-related deaths each year, with ARLD responsible for at least half of cirrhosis cases and constituting the most frequent indication for liver transplantation [2]. Albania, a southeastern European country with historically high hepatitis B virus prevalence [3,4], has witnessed a notable rise in alcohol use [5], creating a distinctive epidemiological landscape in which alcohol and viral hepatitis may synergistically amplify liver injury. Although HBV infection continues to predominate as an etiologic factor in Albania, the proportion of chronic liver disease attributable to alcohol has increased substantially—from 35% in 1995 to 57% in 2005 among HBsAg-negative and anti-HCV-negative patients [3]. Albanian males consume significantly more pure alcohol per year (i.e., 12.5 L per capita) than females (2.6 L), with binge drinking affecting 57.4% of male drinkers and 23.7% of female drinkers, driving a high age-standardized death rate for liver cirrhosis (15.8 per 100,000 for males, 6.2 for females) and an alcohol-attributable fraction of 70.3% for males and 45.6% for females [6]. The high prevalence of alcohol use disorders (5.9%) and dependence (3.4%) underscores the need for integrated healthcare approaches, including early detection, screening, and treatment, to prevent advanced liver disease and reduce the healthcare burden. Moreover, unrecorded alcohol comprises an estimated 18.4% of per capita consumption in the WHO European region [7] (33.3% in Albania), frequently in the form of home-distilled fruit spirits, such as rakia [8]. Produced outside regulatory frameworks, these beverages may contain elevated heavy-metal levels [9], potentially exacerbating hepatotoxicity and heightening the risk of advanced ARLD.

Despite its escalating impact, ARLD remains insufficiently studied in Albania. Noninvasive diagnostic tools, including the Fibrosis-4 Index (FIB-4) [10], the Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) [11], and the Prognostic Nutritional Index (PNI) [12], have gained traction as alternatives to liver biopsy for evaluating fibrosis in patients with diverse etiologies, yet their accuracy in ARLD-specific cohorts, within HBV-endemic settings, such as Albania, remains poorly characterized. The present study aims to provide a first assessment of the clinical characteristics of ARLD in Albania and to examine the utility of FIB-4, APRI, and PNI for fibrosis staging in this population. By filling this knowledge gap, our findings may guide evidence-based approaches to clinical management and inform targeted public health initiatives in Albania where both viral hepatitis and alcohol misuse continue to pose substantial threats to liver health.

2. Materials and Methods

This cross-sectional study was conducted at “Mother Theresa” University Hospital from January 2020 to December 2022, enrolling adults (≥18 years) diagnosed with ARLD and admitted to the Department of Gastroenterology. Eligibility required a confirmed diagnosis of ARLD based on comprehensive biochemical indices, imaging findings and clinical presentation. Exclusion criteria included acute liver failure, active malignancies, pregnancy, and incomplete clinical or laboratory data. Written informed consent was obtained from all participants. The study adhered to the Declaration of Helsinki and received approval from the University of Medicine Tirana ethics committee (Approval No. 9, Nr Prot. 472/5, issue date: 22 February 2024).

2.1. Liver Disease Classification

Liver disease severity was stratified into mild and advanced stages based on an integrated clinial evaluation of imaging findings, biochemical markers, and clinical features by experienced hepatologists. Mild ARLD was defined by the presence of hepatic steatosis graded S1–S2 on abdominal ultrasound, characterized by increased echogenicity without signs of significant fibrosis or cirrhosis, coupled with biochemical markers indicative of early-stage disease (elevated but not markedly abnormal ALT and AST, bilirubin within normal or mildly elevated limits, and platelet counts within the normal range). Advanced LD was characterized by significant fibrosis (F3–F4) or cirrhosis on imaging, elevated AST/ALT ratio (>1), hyperbilirubinemia, thrombocytopenia (<150 × 10³/µL), and the presence of clinical features of decompensation or portal hypertension (e.g., varices, ascites, encephalopathy). Patients were evaluated independently by two hepatologists to ensure consistency in classification. In cases of discordance, a consensus meeting was held to finalize the LD severity classification. The inter-class correlation coefficient (ICC) for LD severity classification between evaluators was 0.85 (95% CI: 0.80–0.90), indicating excellent agreement.

2.2. Data Collection

Comprehensive data were gathered using standardized case report forms. Sociodemographic variables included age, sex, residence (urban/rural), socioeconomic status (SES, categorized as middle or low based on income, education, and occupation), education level (primary, secondary, or tertiary), emigration status, and civil status (single, married/relationship, separated, and widowed). Clinical variables encompassed history of alcohol use disorder (AUD), additional substance use disorder (SUD), comorbidities, and abuse profiles (AUD only vs. AUD + SUD). Biochemical assessments comprised liver function markers (ALT, AST, GGT, alkaline phosphatase [FA], bilirubin, albumin), renal markers (azotemia, creatinine), hematological markers (platelet count [PLT], white blood cell count [WBC], hemoglobin [HGB]), and lipid and metabolic markers (cholesterol, triglycerides). Abdominal ultrasound evaluated steatosis grade (S1–S4), the presence of cirrhosis, and liver texture (homogeneous/heterogeneous).

2.3. Nutritional and Fibrosis Indices

PNI was calculated to evaluate the nutritional and immune status of patients. The PNI was derived using the following formula:

$$\mathrm{P}\mathrm{N}\mathrm{I}=10\times \mathrm{A}\mathrm{l}\mathrm{b}\mathrm{u}\mathrm{m}\mathrm{i}\mathrm{n} (\mathrm{g}/\mathrm{d}\mathrm{L})+0.005\times \mathrm{T}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l} \mathrm{L}\mathrm{y}\mathrm{m}\mathrm{p}\mathrm{h}\mathrm{o}\mathrm{c}\mathrm{y}\mathrm{t}\mathrm{e} \mathrm{C}\mathrm{o}\mathrm{u}\mathrm{n}\mathrm{t} (/{\mathrm{m}\mathrm{m}}^3)$$

Serum albumin was measured using an automated colorimetric assay, while the total lymphocyte count was obtained from a standard complete blood count with differential. The severity of hepatic fibrosis was estimated using two validated noninvasive indices, namely the FIB-4 index and the APRI. The FIB-4 index was calculated using the following formula:

$$\mathrm{F}\mathrm{I}\mathrm{B}-4={\displaystyle \frac{\mathrm{A}\mathrm{g}\mathrm{e} \left(\mathrm{y}\mathrm{e}\mathrm{a}\mathrm{r}\mathrm{s}\right)\times \mathrm{A}\mathrm{S}\mathrm{T} (\mathrm{I}\mathrm{U}/\mathrm{L})}{\mathrm{P}\mathrm{l}\mathrm{a}\mathrm{t}\mathrm{e}\mathrm{l}\mathrm{e}\mathrm{t} \mathrm{c}\mathrm{o}\mathrm{u}\mathrm{n}\mathrm{t} (\times {10}^3/\mathrm{\mu }\mathrm{L})\times \mathrm{A}\mathrm{L}\mathrm{T} (\mathrm{I}\mathrm{U}/\mathrm{L})}}$$

The APRI score was determined as follows:

$$\mathrm{A}\mathrm{P}\mathrm{R}\mathrm{I}={\displaystyle \frac{\mathrm{A}\mathrm{S}\mathrm{T} (\mathrm{I}\mathrm{U}/\mathrm{L})}{\mathrm{A}\mathrm{S}\mathrm{T} \mathrm{u}\mathrm{p}\mathrm{p}\mathrm{e}\mathrm{r} \mathrm{l}\mathrm{i}\mathrm{m}\mathrm{i}\mathrm{t} \mathrm{o}\mathrm{f} \mathrm{n}\mathrm{o}\mathrm{r}\mathrm{m}\mathrm{a}\mathrm{l} \left(\mathrm{U}\mathrm{L}\mathrm{N}\right)}}\times {\displaystyle \frac{100}{\mathrm{P}\mathrm{l}\mathrm{a}\mathrm{t}\mathrm{e}\mathrm{l}\mathrm{e}\mathrm{t} \mathrm{c}\mathrm{o}\mathrm{u}\mathrm{n}\mathrm{t} (\times {10}^3/\mathrm{\mu }\mathrm{L})}}$$

AST and ALT levels were measured using an enzymatic rate method, with the AST upper limit of normal (ULN) defined based on institutional reference ranges. Platelet counts were obtained from routine hematological assessments. Patients were stratified by FIB-4 and APRI values into low, moderate, or high fibrosis risk categories based on established clinical cut-offs [11,13].

While acknowledging the limitations in sensitivity and specificity of APRI and FIB-4, particularly in intermediate fibrosis stages [14], these indices remain integral to noninvasive liver disease assessment due to their accessibility and cost-effectiveness. Their utilization is especially pertinent in resource-constrained settings, where advanced diagnostic tools may be unavailable. The European Association for the Study of the Liver (EASL) recommends the use of simple noninvasive fibrosis tests, like FIB-4, in primary care settings to improve risk stratification and linkage to care for individuals at risk of liver fibrosis, including those with harmful alcohol use [15]. Similarly, the World Health Organization (WHO) endorses the use of APRI and FIB-4 as reliable tools for assessing hepatic fibrosis, particularly in regions where more advanced diagnostics are inaccessible [16]. In the context of our study, conducted within a resource-limited healthcare system, the selection of APRI and FIB-4 aligns with these international guidelines. Their application facilitates the identification of patients with advanced fibrosis, enabling timely intervention and management. Moreover, their noninvasive nature and reliance on routinely available parameters make them practical for widespread clinical use.

2.4. Statistical Analysis

Continuous variables were summarized as medians with interquartile ranges (IQRs) and compared between mild and advanced ARLD groups using the Mann–Whitney U test. Pearson correlation coefficients were calculated to assess the relationships among biochemical parameters and fibrosis indices, specifically the FIB-4 index and the APRI. To categorize patients based on fibrosis risk, FIB-4 and APRI scores were stratified into low, moderate, and high risk categories according to established clinical cut-offs. Radar plots were generated to visually compare standardized mean values of biochemical markers between mild and advanced ARLD groups, providing a comprehensive overview of biochemical profiles across disease severities. We used multivariate logistic regression to assess the association between socioeconomic status, comorbidities, liver function markers, and the risk of advanced liver disease. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated for each variable, adjusted for age, sex, smoking status, and duration of alcohol use to control for potential confounding factors. Model selection was guided by clinical relevance and Akaike’s information criterion (AIC) to optimize model fit. Continuous variables were assessed for linearity using restricted cubic splines, and collinearity was evaluated using variance inflation factors (VIFs). Goodness of fit was assessed using the Hosmer–Lemeshow test. All statistical tests were two-sided, and a p-value of less than 0.05 was considered statistically significant. All statistical analyses were performed using Rstudio 3.6.0 and SPSS version 16.0 (SPSS Inc., Chicago, IL, USA).

3. Results

3.1. Demographic and Socioeconomic Characteristics

Among 200 enrolled patients, 96.5% (95% CI, 93.3–98.4%) were male, and the majority (83.0% [95% CI, 77.3–87.7%]) had middle socioeconomic status (

Table 1. Sociodemographic and clinical characteristics of patients with mild and advanced liver disease.

Characteristic	All Patients (n = 200)	Mild Liver Disease (n = 157)	Advanced Liver Disease (n = 43)
Sex
Male	193 (96.5) [93.3–98.4]	150 (95.5) [91.4–98.0]	43 (100.0) [–]
Socioeconomic status
Middle SES	166 (83.0) [77.3–87.7]	134 (85.4) [79.2–90.2]	32 (74.4) [60.1–85.6]
Low SES	34 (17.0) [12.3–22.7]	23 (14.6) [9.8–20.8]	11 (25.6) [14.4–39.9]
Residence
Rural	21 (10.5) [6.8–15.3]	16 (10.2) [6.2–15.6]	5 (11.6) [4.6–23.6]
Urban	179 (89.5) [84.7–93.2]	141 (89.8) [84.4–93.8]	38 (88.4) [76.4–95.4]
Migration status
Not emigrated	162 (81.0) [75.1–86.0]	128 (81.5) [74.9–87.0]	34 (79.1) [65.3–89.1]
Emigrated	38 (19.0) [14.0–24.9]	29 (18.5) [13.0–25.1]	9 (20.9) [10.9–34.7]
Education level
Primary	33 (16.5) [11.9–22.1]	23 (14.6) [9.8–20.8]	10 (23.3) [12.6–37.3]
Secondary	142 (71.0) [64.4–77.0]	114 (72.6) [65.3–79.1]	28 (65.1) [50.3–78.0]
Tertiary	25 (12.5) [8.5–17.6]	20 (12.7) [8.2–18.6]	5 (11.6) [4.6–23.6]
Marital status
Single	64 (32.0) [26.0–38.9]	53 (34.0) [26.9–41.6]	11 (25.6) [14.4–39.9]
Married/in relationship	114 (57.0) [50.3–64.0]	86 (55.1) [47.3–62.8]	28 (65.1) [50.3–78.0]
Separated	17 (8.5) [5.3–13.0]	13 (8.3) [4.8–13.4]	4 (9.3) [3.2–20.6]
Widowed	4 (2.0) [0.7–4.7]	4 (2.6) [0.9–6.0]	0 (0.0) [–]
Substance use disorder
Alcohol use disorder	163 (81.5) [75.7–86.4]	125 (79.6) [72.8–85.3]	38 (88.4) [76.4–95.4]
Alcohol + other substance use	37 (18.5) [13.6–24.3]	32 (20.4) [14.7–27.2]	5 (11.6) [4.6–23.6]
Comorbidities
None	122 (61.0) [54.1–67.6]	93 (59.2) [51.4–66.7]	29 (67.4) [52.7–80.0]
≥1 comorbidity	78 (39.0) [32.4–45.9]	64 (40.8) [33.3–48.6]	14 (32.6) [20.0–47.3]

Notes: Data are presented as numbers (percentage [95% confidence interval of percentage]). Socioeconomic status (SES) was classified as middle or low based on income, education, and occupation. Educational levels: primary (1–8 years of education), secondary (9–12 years), and tertiary (12+ years).

). Urban residency prevailed (89.5% [95% CI, 84.7–93.2%]), and most patients had not emigrated (81.0% [95% CI, 75.1–86.0%]). Overall, 71.0% (95% CI, 64.4–77.0%) of participants had achieved a secondary-level education, while only 12.5% (95% CI, 8.5–17.6%) had a tertiary-level education. Regarding liver disease severity, patients with advanced disease were exclusively male, and a larger proportion had a low socioeconomic status compared with those who had mild disease (25.6% vs. 14.6%). Advanced disease patients also exhibited a slightly higher likelihood of being married or in a relationship (65.1% vs. 55.1%) and a lower rate of alcohol-plus-other-substance use (11.6% vs. 20.4%). Comorbidities were reported in 39.0% of participants, though the rate was somewhat lower in the advanced disease cohort (32.6%) than in the mild disease group (40.8%). These findings highlight the predominantly male composition of patients with alcohol-related liver disease in this cohort, an urban-centered demographic profile, and the elevated burden of disease in those of lower socioeconomic status.

3.2. Correlations

Correlations between clinical and biochemical parameters revealed distinct patterns reflective of disease severity and progression (Figure 1). FIB-4 was strongly correlated with AST (r = 0.81), consistent with the known predominance of AST elevation in advanced ARLD. FIB-4 and APRI were inversely correlated with platelet count (r = −0.61 and r = −0.59, respectively), supporting their role in assessing hepatic fibrosis, as progressive liver disease is associated with thrombocytopenia. APRI exhibited a moderate correlation with ALT (r = 0.47), whereas its correlation with AST was stronger, reinforcing its diagnostic relevance in ARLD. The PNI demonstrated a strong positive correlation with albumin (r = 0.77), indicating that lower PNI scores were associated with declining nutritional status and impaired hepatic synthetic function. PNI was inversely correlated with FIB-4 (r = −0.27) and APRI (r = −0.24), suggesting a relationship between fibrosis severity and nutritional depletion. Bilirubin correlated positively with FIB-4 (r = 0.49), AST (r = 0.51), and GGT (r = 0.51), reflecting its utility as a marker of hepatic dysfunction in ARLD. GGT, a known indicator of alcohol-induced liver injury, showed a strong correlation with AST (r = 0.61) and a moderate correlation with ALT (r = 0.37), aligning with expected patterns of alcohol-related hepatocellular injury. BUN and creatinine were weakly correlated with liver function markers, though BUN exhibited minor associations with bilirubin and liver enzymes, potentially indicating early renal impairment in patients with more advanced disease. Serum cholesterol demonstrated a moderate correlation with bilirubin (r = 0.31) but had no significant associations with fibrosis markers, suggesting that dyslipidemia may not be a primary contributor to ARLD progression in this population.

3.3. Clinical Profile and Fibrosis Risk

Key differences emerged between those with mild versus advanced liver disease, particularly in terms of age, alcohol consumption patterns, hematologic markers, glucose metabolism, liver function, and fibrosis indices (

Table 2. Clinical and laboratory characteristics by liver disease stage.

Characteristic	All Patients (n = 200)	Mild Liver Disease (n = 157)	Advanced Liver Disease (n = 43)	p-Value †
Age (years)	45 (44–49)	44 (43–47)	51 (48–56)	*
Alcohol Consumption 1
Duration (years)	12 (12–15)	10 (10–13)	18 (15–20)	**
Units per week	24 (24–28)	24 (24–28)	24 (20–32)
Volume (mL)	600 (600–700)	600 (600–700)	600 (500–800)
Smoking
Pack-years	30 (30–40)	30 (30–40)	30 (30–40)
Duration (years)	15 (15–20)	15 (15–18)	20 (20–25)	**
Hematologic Markers
White blood cell count (109/L)	7.4 (7.0–7.8)	7.8 (7.5–8.3)	6.2 (5.7–7.3)
Hematocrit (%)	46 (46–47)	47 (46–47)	44 (41–46)	**
Hemoglobin (g/L)	150 (149–153)	151 (150–154)	139 (134–149)	**
Platelet count (109/L)	210 (193–220)	220 (210–237)	144 (130–183)	**
Glucose Metabolism
Blood glucose (mmol/L)	4.8 (4.6–4.9)	4.6 (4.5–4.9)	5.5 (5.3–7.0)	**
Renal Function
Blood urea nitrogen (mmol/L)	7.3 (7.0–7.9)	7.5 (7.1–8.2)	6.4 (6.1–8.3)
Serum creatinine (µmol/L)	67 (65–68)	67 (66–69)	66 (63–72)
Liver Enzymes
Alanine aminotransferase (U/L)	36 (33–41)	34 (29–40)	48 (37–66)	*
Aspartate aminotransferase (U/L)	39 (33–44)	33 (29–39)	83 (53–96)	**
Alkaline phosphatase (U/L)	66 (64–71)	66 (62–71)	66 (63–81)
Gamma-glutamyl transferase (U/L)	66 (54–78)	49 (42–64)	212 (125–341)	**
Bilirubin and Lipids
Total bilirubin (µmol/L)	14 (12–15)	13 (11–14)	19 (16–27)	**
Total cholesterol (mmol/L)	5.0 (4.7–5.1)	4.9 (4.7–5.1)	5.2 (4.7–5.9)
Triglycerides (mmol/L)	1.3 (1.2–1.4)	1.3 (1.2–1.5)	1.4 (1.1–1.9)
Protein and Coagulation Markers
Total protein (g/L)	70 (70–73)	70 (70–74)	70 (66–70)
Serum albumin (g/L)	40 (40–41)	40 (40–41)	32 (31–37)	**
Nutritional and Fibrosis Indices
PNI 2	50 (50–52)	52 (51–53)	44 (42–49)	**
APRI 3	0.5 (0.5–0.7)	0.4 (0.4–0.5)	1.6 (1.0–2.6)	**
FIB-4 Index 4	1.4 (1.3–1.8)	1.2 (1.1–1.4)	4.2 (2.5–6.5)	**

¹ One unit of alcohol = 10 g ethanol. ² PNI (Prognostic Nutritional Index): 10 × albumin (g/dL) + 0.005 × total lymphocyte count (/mm³). Lower values indicate poorer nutritional/immune status. ³ The APRI (AST-to-Platelet Ratio Index) also estimates fibrosis risk; higher values suggest more advanced fibrosis. ⁴ The FIB-4 (Fibrosis-4) index estimates fibrosis severity. ^† p-values were calculated using the Mann–Whitney U test. Statistically significant differences are denoted as p ≤ 0.001 (**) and p ≤ 0.05 (*). Non-significant differences are left blank.

). The median age of the cohort was 45 years (IQR, 44–49), with patients in the advanced liver disease group being significantly older (51 years [48–56]) than those with mild disease (44 years [43–47]). The duration of alcohol consumption was also notably longer in patients with advanced disease (18 years [15–20] vs. 10 years [10–13]), though the median weekly alcohol intake (24 units) and daily volume (600 mL) were similar across both groups. There was a high burden of tobacco exposure, with a median of 30 pack-years and 15–20 years of smoking history.

Notably, patients with advanced liver disease had a longer smoking duration (20 years [20–25] vs. 15 years [15–18]), suggesting a potential cumulative impact on disease progression. Patients with advanced liver disease exhibited a lower white blood cell count (6.2 × 10⁹/L [5.7–7.3] vs. 7.8 × 10⁹/L [7.5–8.3]) and lower hematocrit (44% [41–46] vs. 47% [46–47]), consistent with bone marrow suppression or hypersplenism. Hemoglobin levels were lower in advanced disease (139 g/L [134–149] vs. 151 g/L [150–154]), potentially reflecting chronic inflammation or anemia of the liver. The platelet count was markedly reduced in patients with advanced disease (144 × 10⁹/L [130–183] vs. 220 × 10⁹/L [210–237]), consistent with progressive fibrosis and portal hypertension. Patients with advanced liver disease had higher fasting blood glucose levels (5.5 mmol/L [5.3–7.0] vs. 4.6 mmol/L [4.5–4.9]), suggesting impaired glucose regulation. BUN and serum creatinine values were comparable between groups, though a slight reduction in BUN in the advanced disease group (6.4 mmol/L [6.1–8.3] vs. 7.5 mmol/L [7.1–8.2]) may indicate early alterations in renal function. Markers of liver injury and cholestasis showed substantial elevations in advanced disease. Aspartate aminotransferase (AST) levels were nearly 2.5-fold higher in advanced disease (83 U/L [53–96] vs. 33 U/L [29–39]), and GGT was fourfold higher (212 U/L [125–341] vs. 49 U/L [42–64]). ALT levels were also elevated (48 U/L [37–66] vs. 34 U/L [29–40]), though the AST-to-ALT ratio remained consistent with alcohol-related liver injury.

Total bilirubin was significantly elevated in advanced disease (19 µmol/L [16–27] vs. 13 µmol/L [11–14]), reflecting worsening hepatic dysfunction and impaired bilirubin clearance. Cholesterol and triglyceride levels were comparable between groups. Serum albumin levels were markedly lower in advanced disease (32 g/L [31–37] vs. 40 g/L [40–41]), consistent with deteriorating hepatic synthetic function. Total protein levels showed a slight decline (70 g/L [66–70] vs. 70 g/L [70–74]), though the INR remained stable across disease groups. Markers of fibrosis and nutritional status showed the most pronounced differences. Specifically, FIB-4 was 3.5 times higher in advanced disease (4.2 [2.5–6.5] vs. 1.2 [1.1–1.4]), confirming its utility in distinguishing disease severity.

APRI scores were also substantially elevated (1.6 [1.0–2.6] vs. 0.4 [0.4–0.5]). The PNI was significantly lower in advanced disease (44 [42–49] vs. 52 [51–53]), highlighting the nutritional deterioration that accompanies progressive liver dysfunction.

A comparative analysis of clinical and biochemical parameters in patients with mild versus advanced ARLD is visually represented in Figure 2A. This radar plot illustrates the relative differences across key biomarkers, demonstrating distinct metabolic, hepatic, and hematologic alterations between disease stages. Patients with advanced liver disease (red area) exhibited markedly higher levels of AST, ALT, GGT, and total bilirubin, consistent with progressive hepatocellular injury and cholestasis. The elevation in AST and GGT is particularly pronounced, aligning with the expected pattern in alcohol-related liver injury. Fibrosis indices, including the FIB-4 Index and APRI, were significantly higher in patients with advanced disease, reflecting greater degrees of hepatic fibrosis. The most striking increase is observed in FIB-4, which aligns with its well-established role in noninvasive fibrosis assessment.

Conversely, platelet count, a surrogate marker of portal hypertension and advanced fibrosis, was substantially lower in the advanced disease group, further reinforcing the presence of cirrhosis-related thrombocytopenia. The PNI and serum albumin levels were notably lower in patients with advanced disease, indicating worsening nutritional status and declining hepatic synthetic function. These findings underscore the progressive catabolic state and malnutrition commonly observed in advanced liver disease. Glucose levels were higher in patients with advanced disease, suggesting increased insulin resistance and metabolic dysregulation, both of which are frequently observed in chronic liver disease. Markers of renal function, including BUN and serum creatinine, remained largely similar across disease groups, suggesting that overt renal dysfunction was not a distinguishing feature in this cohort. Total cholesterol and triglyceride levels showed minimal differences, further supporting the hypothesis that dyslipidemia may not be a primary driver of disease progression in ARLD.

Figure 2B presents the distribution of fibrosis risk (FIB-4), nutritional risk (PNI), and liver fibrosis severity (APRI) across patients with mild and advanced ARLD. The data reveal a progressive shift in risk classification as liver disease advances, with significant differences observed across all three indices. The proportion of patients at low risk for fibrosis (F0–F1) was significantly higher in the mild disease group (95.1%) compared to those with advanced disease (4.9%). In contrast, among patients with high-risk advanced fibrosis (F3–F4), 58.5% had advanced liver disease, while only 41.5% of patients in this category remained classified as mild, indicating a strong association between FIB-4 and liver disease severity. Nutritional status, as assessed by the PNI, declined with disease progression. While 93.5% of patients in the mild disease group had no nutritional risk, only 6.5% exhibited early signs of malnutrition.

However, among those at high risk of severe malnutrition, 52.2% had advanced liver disease, confirming the association between progressive hepatic dysfunction and declining nutritional status. The APRI further stratified patients according to fibrosis severity, demonstrating a clear gradient of worsening disease. Among those classified as low risk (minimal fibrosis), 92.6% had mild liver disease, whereas in the high-risk cirrhosis category, 60% had advanced disease. This pattern underscores the clinical utility of APRI in distinguishing mild fibrosis from cirrhotic-stage disease.

3.4. Association of Socioeconomic, Nutritional, and Liver Fibrosis Markers with Advanced Liver Disease

After adjustment for age, sex, smoking status, and duration of alcohol use, lower PNI was significantly associated with higher odds of advanced ARLD (OR 0.95, 95% CI 0.91–0.99, p = 0.014), suggesting nutritional status may influence disease progression (Figure 3). Higher APRI scores were associated with increased risk of advanced ARLD (OR 1.27, 95% CI 0.71–2.26) and FIB-4 showed a similar trend (OR 1.10, 95% CI 0.81–1.51), though neither reached statistical significance. Lower educational attainment (primary vs. higher education: OR 0.50, 95% CI 0.16–1.60; secondary vs. higher education: OR 0.57, 95% CI 0.12–2.83), and lower socioeconomic status were not significantly associated with disease progression (OR 1.24, 95% CI 0.39–3.94).

4. Discussion

This cross-sectional analysis provides essential insights into the clinical characteristics and progression of ARLD in Albania, a country uniquely affected by endemic HBV [3], widespread unregulated alcohol consumption [17], and malnutrition in many forms [18]. While international guidelines for ARLD management emphasize early detection and multidisciplinary care [19,20], Albania’s unique epidemiological context, marked by overlapping metabolic, viral, and socioeconomic risk factors necessitates tailored approaches. Our findings underscore the need for context-specific strategies to address the growing burden of ARLD.

Advanced ARLD in Albania is linked with prolonged alcohol use (median 18 years), consistent with global patterns in which cumulative alcohol intake drives fibrosis progression [20]. A higher representation of advanced ARLD was observed among patients with lower socioeconomic status, suggesting economic barriers potentially limiting healthcare access and driving consumption of unregulated homemade spirits, which constitute a significant proportion of alcohol intake in Southeast Europe. Hammer et al. [7] suggests that this may be driven by economic hardship. In a recent study in Albania, these unregulated beverages frequently contained contaminants, such as heavy metals [9], exacerbating hepatotoxicity and increasing vulnerability to liver injury.

Although there are no other studies on this topic in Albania to compare our results with, compared to the wider literature, the biochemical profile of advanced ARLD, marked by elevated AST, GGT, and bilirubin, aligns with the mitochondrial dysfunction and cholestasis patterns observed in previous studies [21,22]. However, thrombocytopenia and hypoalbuminemia were more pronounced than in Western studies, likely reflecting synergistic insults from persistent alcohol abuse, HBV, and protein–energy malnutrition [23]. Indeed, 52.2% of patients with severe malnutrition (PNI < 40) had advanced ARLD, consistent with data showing that PEM increases mortality risk by 2.3-fold in cirrhotic patients [24]. This underscores the clinical importance of malnutrition as a prognostic factor for disease severity and progression for ARLD. Patients with ARLD, in general, exhibit characteristic but non-diagnostic laboratory abnormalities [21,22]. A hallmark finding is moderately elevated transaminases with an AST/ALT ratio > 1 (often > 2), distinguishing ARLD from other liver diseases [25,26,27,28]. Serum AST rarely exceeds eight times the upper limit of normal, while ALT remains below five times the upper limit. This disproportionate AST elevation is attributed to pyridoxal 5′-phosphate deficiency in alcoholics [28], impairing ALT activity.

An AST/ALT ratio > 2 strongly suggests ARLD, as values this high are rare in other liver diseases [27]. In biopsy-confirmed cases, >90% of patients with AST/ALT ≥ 2 had ARLD, increasing to >96% when the ratio was ≥3 [29]. GGT is frequently elevated (8–10× normal) [30] but is not specific to ARLD, as it may be elevated in biliary disease or with certain medications [22,30,31]. Elevated bilirubin suggests decompensated cirrhosis or alcoholic hepatitis in non-cirrhotic patients, while low albumin levels may indicate malnutrition or cirrhosis.

Albania’s ARLD burden is likely underestimated due to underutilized noninvasive screening. There are no current guidelines, but according to the British Society of Gastroenterology and the British Association for the Study of the Liver, fibrosis assessment is recommended for individuals consuming >112 g/week of alcohol with metabolic comorbidities [20], a threshold exceeded by 71% of our sample. However, primary care providers lack training in APRI/FIB-4 interpretation, delaying specialist referrals. Combining FIB-4 screening with HBV vaccination has the potential to reduce cirrhosis-related hospitalizations. Future interventions should integrate such approaches to strengthen primary care by enhancing provider awareness and training, thereby improving the early identification and timely referral of high-risk patients.

Moreover, regulating homemade alcohol, a source of methanol and fusel oils, is paramount. Taxation and quality controls, as proposed in WHO frameworks [32], could reduce hepatotoxicity while funding public health campaigns. Notably, 88.4% of advanced ARLD patients reported exclusive alcohol use (no polysubstance misuse), emphasizing the need for combined AUD-specific counseling and therapy [33], which are underprescribed despite evidence of safety in cirrhosis in our sample. Our study also coincides with the release of the US Surgeon General advice on alcohol risk and cancer, to better inform the public of this relationship and offers key recommendations to reduce alcohol-related cancers [34].

Furthermore, malnutrition was evident in advanced ARLD, as lower PNI and hypoalbuminemia highlight the interplay between hepatic dysfunction and malnutrition. Management strategies integrating nutritional support to address sarcopenia and micronutrient deficiencies should be routine components of ARLD treatment protocols. Although renal function parameters, such as serum creatinine and blood urea nitrogen, did not differ significantly between mild and advanced ARLD groups, subtle renal impairment may still be present, necessitating careful monitoring for hepatorenal syndrome. The results of the multivariate models suggest a potential role for nutritional status and liver fibrosis markers in advanced ARLD, but the wide confidence intervals and lack of statistical significance for most associations underscore substantial uncertainty. The significant association between lower PNI and higher disease risk may reflect a real effect, but given the study’s limited power, this finding should be interpreted with caution. A key limitation is the absence of HBV status data, which may underestimate disease severity, as undiagnosed HBV coinfection could exacerbate fibrosis progression and liver dysfunction. The trends observed for APRI and FIB-4 suggest a possible association with disease progression, yet the inconsistency in statistical significance highlights the risk of spurious findings in underpowered analyses.

Some additional limitations which merit consideration in our study are the predominantly male sample, which constrains the generalizability of our results to female populations. Furthermore, the study’s cross-sectional design precludes definitive causal inferences, while residual confounding may influence some observed associations despite multivariable adjustments. The monocentric nature of our study may limit the generalizability of the findings beyond the specific clinical setting in which the data were collected. Additionally, the study’s statistical power constraints underscore caution in interpreting nonsignificant trends, particularly regarding APRI and FIB-4 indices. The dual role of serum albumin as an indicator of both hepatic functional reserve (e.g., within the Child–Pugh classification) and nutritional status may introduce interpretative bias; this overlap should be acknowledged as a limitation in discerning its independent association within multivariable models. Replicating these results in larger, more diverse cohorts would bolster their validity and clarify the biological underpinnings of advanced ARLD. Further investigation of the mechanisms linking severe malnutrition and accelerated fibrosis progression may also inform more targeted treatment strategies; in this context, future larger studies, incorporating HBV data, hepatocellular carcinoma prevalence and survey-based data could enhance the contextual understanding of affected populations and strengthen the clinical relevance of the observed associations.

5. Conclusions

This first clinical assessment of ARLD in Albania highlights APRI, FIB-4, and PNI as feasible, cost-effective markers for disease staging in resource-limited settings. The high burden of advanced ARLD among socioeconomically disadvantaged individuals underscores the need for targeted interventions integrating alcohol regulation, nutritional support, and noninvasive fibrosis screening. Strengthening primary care through systematic screening and early referral pathways is critical. Future longitudinal studies are needed to refine the risk stratification and inform evidence-based prevention and treatment strategies in Albania and similar settings.