Nutrition in Hepatocellular Carcinoma: Pathophysiological Insights, Impact, and Implications for Clinical Practice

ABSTRACT

Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related mortality worldwide. Malnutrition is highly prevalent among people living with HCC and has a substantial impact on morbidity and mortality. Nutrition influences the development of HCC and is also a consequence of chronic liver disease and liver cancer. Routine screening and nutritional assessment using validated tools, along with evaluation of muscle mass and functional status, are essential in the optimal care of patients with HCC. Nutritional interventions may change throughout the disease trajectory depending on the stage of HCC, the severity of liver cirrhosis, and the overall treatment options and intent. Evidence supports the use of oral nutritional supplements, branched‐chain amino acids, exercise interventions, and the preferential use of enteral over parenteral nutrition. Optimizing nutrition is integral to HCC management across all disease stages and is best accomplished with a multidisciplinary team to individualize the nutritional care across the disease continuum. In this review, we summarize current evidence on the impact and role of nutritional therapy in HCC and provide actionable recommendations for clinical practice. We highlight the current challenges and provide future directions for future HCC nutritional care pathways.

Nutritional management across the HCC treatment spectrum. Abbreviations: E, energy intake; C, carbohydrates; P, proteins; L, lipids; TEE, total energy expenditure; ONS, oral nutritional supplements; BCAA, branched‐chain amino acids; EN, enteral nutrition; PN, parenteral nutrition; esp, especially; SGA, Subjective Global Assessment; GLIM, Global Leadership Initiative on Malnutrition; MNA‐SF, Mini Nutritional Assessment Short Form; PG‐SGA SF, Patient‐Generated Subjective Global Assessment Short Form; NRS, Nutritional Risk Screening; MUST, Malnutrition Universal Screening Tool.

1. Introduction

Hepatocellular carcinoma (HCC), a predominant cause of malignancy, ranks as the third leading cause of cancer‐related mortality worldwide [1]. With a 5‐year survival rate of 18% and 2.3% in metastatic advanced disease [2], HCC represents a major global health burden largely due to its asymptomatic presentation and often late‐stage diagnosis. Together with shifting etiological patterns, the incidence and mortality of HCC are now increasingly driven by the rising global prevalence of an aging population. Conditions such as metabolic syndrome, obesity, type 2 diabetes mellitus and nonalcoholic fatty liver disease are emerging as key drivers of HCC, surpassing viral etiologies like hepatitis B and C [3]. Unlike other malignancies, HCC poses a unique and complex nutritional challenge due to its development within the context of chronic liver disease. Malnutrition, sarcopenia, and metabolic derangements are particularly prevalent in patients with HCC due to the compounded effects of underlying cirrhosis and its associated sequelae—hepatic dysfunction, impaired nutrient metabolism and tumor‐related catabolism [4]. Whereas nutritional compromise in other malignancies is often secondary to advanced disease or treatment‐related side effects, in HCC, malnutrition initiates, and worsens along with the disease [5]. Malnutrition—one of the most important driving factors of mortality and morbidity in HCC patients [6]—therefore represents a key target for clinical intervention.

Optimal management involves a multidisciplinary approach including hepatologists, oncologists, surgeons and dieticians [7]. Given the nutritional burden in HCC, the early and ongoing involvement of dieticians is essential in ensuring favorable patient outcomes [8].

Although early diagnosis and treatment is critical, primary intervention strategies—particularly proactive nutritional strategies—may prove a worthy adjunct in optimizing the care and improving mortality and morbidity in patients with HCC. This review aims to synthesize current evidence on the role of nutrition in HCC patients, address mechanistic links between dietary factors and hepatocarcinogenesis, evaluate dietary and nutritional risk factors and their impact on prognosis, and assess current clinical interventions with a focus on optimizing patient outcomes and informing future research directions.

2. Pathophysiological Basis of Malnutrition in HCC

Malnutrition in HCC arises from a complex interplay of hepatic dysfunction, nutritional malabsorption, inflammation, hypermetabolism, and cancer‐related cachexia (Figure 1).

FIGURE 1.

Pathophysiology of malnutrition in HCC.

The three main macronutrients and their absorption—carbohydrates, proteins, fats—as well as micronutrients, are all affected in HCC due to the liver's central role in metabolism.

Hepatic dysfunction in HCC precipitates significant disturbances in carbohydrate metabolism, largely owing to the development of insulin resistance, impaired glucose tolerance, reduced glycogen synthesis and storage, and an early shift towards gluconeogenesis [9]. In the insulin‐resistant liver, dysregulated hepatic glucose production persists even in the postprandial fed state, due to the selective disruption of the insulin signaling cascade. This results in the inability of insulin to downregulate gluconeogenic gene expression, while its lipogenic effects remain unopposed—thereby promoting both hyperglycemia and hepatic steatosis [10]. These metabolic alterations contribute to the catabolic characteristics of HCC and further compound the nutritional burden in these patients.

In HCC, protein catabolism precipitates an “accelerated starvation state” and negative nitrogen balance due to hepatic dysfunction. The diseased liver's limited glycogen reserves are rapidly depleted because of a metabolic shift towards amino acid utilization for gluconeogenesis. It preferentially mobilizes amino acids from skeletal muscle to sustain hepatic glucose output and acute‐phase reactant synthesis, rather than preserving lean body mass. This sustained catabolic drive, compounded by impaired glycogen synthesis and persistent gluconeogenesis [11], is a defining feature of advanced liver disease and a central contributor to malnutrition in HCC. Thus, reduced hepatic protein synthesis and increased peripheral protein degradation further exacerbate nutritional decline via promotion of sarcopenia, impaired immune competence, delayed tissue repair, and, subsequently, increased vulnerability to HCC mortality and morbidity.

Impaired lipid metabolism in HCC is predominantly driven by reduced bile salt synthesis and cholestasis, resulting in malabsorption of long‐chain fatty acids and fat‐soluble vitamins (A, D, E, and K) [12]. As bile acids are essential for micelle formation and intestinal fat absorption, underlying cirrhosis or tumor‐related biliary obstruction in HCC significantly compromises lipid uptake resulting in significant energy deficits due to the caloric density of fats, and clinically significant micronutrient deficiencies—manifesting as coagulopathy (vitamin K), osteomalacia (vitamin D), visual disturbances (vitamin A), neuromuscular dysfunction (vitamin E) [13], increased risk of hepatic encephalopathy, sarcopenia, and frailty (zinc). Additionally, altered lipid metabolism contributes to systemic metabolic derangements, including lipotoxicity and inflammatory activation, which further exacerbate hepatic dysfunction and nutritional decline [13].

Furthermore, chronic systemic inflammation in HCC, mediated by pro‐inflammatory cytokines (TNF‐α and IL‐6) drives anorexia, muscle catabolism, and hypermetabolic states that culminate in cancer‐associated cachexia [14]. Hypermetabolism, prevalent in patients with HCC, is characterized by increased resting energy expenditure, which further widens the gap between nutritional intake and metabolic demand, accelerating nutritional decline [15]. Cachexia in HCC is marked by progressive, involuntary weight loss and skeletal muscle wasting. Unfortunately, the liver acts both as a source and target of inflammatory mediators, thereby amplifying metabolic dysregulation [14]. Sarcopenia—a core clinical manifestation of cachexia and a key component of malnutrition in cirrhosis—is highly prevalent in 60% of those with HCC [16], often emerging early in the disease course and independently associated with poor clinical outcomes. This is due to reduced hepatic and skeletal muscle protein synthesis, enhanced proteolytic activity, hyperammonemia, mitochondrial dysfunction, and anabolic resistance [17].

Such complications are strongly associated with poorer outcomes in HCC patients—increased hospitalizations, increased length of stay, and higher mortality rates. As these disease‐related complications progress, the ability to maintain adequate nutrition declines [8]. The exacerbated complications of cirrhosis including encephalopathy, ascites, and hepatorenal syndrome further reduce oral intake and nutrient absorption [15], perpetuating a self‐reinforcing cycle of malnutrition, functional decline, and adverse outcomes. This underscores the importance of optimizing nutritional status and timely intervention of nutritional strategies to be integrated into standard care pathways in HCC management [5].

2.1. Malnutrition in HCC: Prevalence and Impact

Considering such elaborate interconnectedness in terms of pathophysiology, it is unsurprising that there is a substantial prevalence of malnutrition in HCC. In a retrospective cohort study involving 360 cirrhotic patients with HCC, malnutrition was found in nearly half of the patients (179 patients, 49.7%) based on the Global Leadership Initiative on Malnutrition (GLIM) criteria including reduced muscle mass [18]. In a similar study by Omiya et al. involving 293 HCC patients undergoing liver resection, 116 (40%) had moderate and 47 (16%) had severe malnutrition, totally exceeding half of the patients (56%) [19]. In a meta‐analysis of 57 studies involving 9790 HCC patients by Guo et al. [20], the pooled prevalence of sarcopenia alone was 41.7% (95% CI 36.2–47.2%).

Of greater concern is the fact that malnutrition has a significant impact on overall survival, recurrence‐free survival, operative risks, and response to therapy against HCC. In the mentioned Omiya et al.'s study, patients with severe malnutrition had significantly reduced median overall survival (43 vs. 129 months) and recurrence‐free survival (20 vs. 54 months), compared to those without [19]. In another study, regardless of Barcelona clinic liver cancer (BCLC) stages, GLIM‐diagnosed malnutrition was associated with reduced postoperative overall survival, and multivariate analysis further reinforced its role as an independent predictor of survival [21]. In Guo et al.'s meta‐analysis [20], sarcopenia was proven to yield higher postresection severe complications, greater drug toxicity, reduced tumor objective response rate, increased recurrence, and poorer survival in HCC patients. As such, malnutrition must never be overlooked in HCC.

2.2. Nutritional Screening and Assessment in HCC

Nutritional screening and assessment are integral to the management of HCC, given the high prevalence of malnutrition and its established association with morbidity and mortality. Several validated tools are available for nutritional risk screening, each with specific advantages and limitations. Among the most widely applied in patients with HCC and underlying cirrhosis are the Nutrition Risk Screening 2002 (NRS‐2002) [22], the Malnutrition Universal Screening Tool (MUST) [23], the Subjective Global Assessment (SGA) and its patient‐generated variant (PG‐SGA) [24] as well as the GLIM criteria [25]. The American Gastroenterological Association supports the routine application of these tools in chronic liver disease, and comparative studies in HCC populations have shown substantial concordance between NRS‐2002, PG‐SGA, and GLIM, with the latter two often identifying a greater prevalence of malnutrition [26]. The available nutritional screening and assessment tools used in chronic liver disease and HCC are summarized in Table 1.

TABLE 1.

Screening and assessment tools for malnutrition and use in the context of HCC.

Screening tool	Primary target	Components and thresholds	Advantages	Limitations	Use in HCC context
Malnutrition Universal Screening Tool (MUST) [23]	Rapid general screening for adult patients in community, outpatient, inpatient	BMI, % weight loss, acute disease effect; ≥1 medium risk; ≥2 high risk	Simple, quick, easy to recall, universal use even in the community setting	Ascites/edema would increase BMI and might cause risk underestimation	Use during surveillance visits every 6 months (EASL/AASLD/BSG/NICE). If +: SGA, GLIM
Nutritional Risk Screening (NRS)‐2002 [22]	Inpatient screening, both acute and chronic illnesses	BMI, weight loss within 3 months, reduced dietary intake within 1 week, ICU/disease severity; ≥3 nutritional risk	Considers stress due to illness/medical procedure, can be used periprocedurally, suited for hospital setting	Subjective scoring for severity, ascites/edema would increase BMI and might cause risk underestimation	Use during acute decompensation, preresection/transplant, pre‐TACE/Y‐90 as part of multidisciplinary care (EASL, BSG). If +: SGA, GLIM
Patient‐Generated Subjective Global Assessment Short Form (PG‐SGA SF) [24]	Screening/monitoring, patient‐reported, for oncology patients of all ages	Weight, intake, symptom burden, function; ≥5 malnutrition	Encourages self‐monitoring, evaluates symptoms suited for oncology patients	Requires patient literacy/participation, can be misinterpreted, can overemphasize transient symptoms	Use during systemic/palliative therapy to detect early decline, guides rapid adjustment according to symptoms and nutrition If +: SGA, GLIM, address symptoms, nutritional support
Mini Nutritional Assessment Short Form (MNA‐SF) [27]	Assessment for older adults ≥ 65 years old, inpatient/community setting	Anthropometrics (BMI, arm/calf circumference, weight loss), mobility, stress/acute disease, neuropsychological problems, food intake; 8–11 risk; < 8 malnutrition	Validated for older adults, includes functional and cognitive problems, does not need advanced measurement	Not routinely used for younger patients, ascites/edema would increase BMI and might cause risk underestimation	Recommended by ESPEN for geriatric patients, AASLD recommends nutritional assessment without naming tool ‐ MNA‐SF can be used when combined with muscle mass
Subjective Global Assessment (SGA) [28]	Global assessment at bedside	Weight change, dietary intake, gastrointestinal symptoms, function, exam: fat, muscle, edema, ascites; A no sign; B mild–moderate; C severe	Considers muscle/fat/fluid composition, gold standard clinical assessment	Requires longer time and need trained assessor	Use before regional/systemic therapy/transplant/resection as part of multidisciplinary (EASL, BSG) and comprehensive (AASLD) care
Global Leadership Initiative on Malnutrition (GLIM) [25]	Diagnosis of malnutrition and grading after initial screening with other tools	≥ 1 phenotypic (weight loss, low BMI, low muscle mass) + ≥1 etiologic (reduced intake/absorption, inflammation); moderate/severe based on phenotypic criteria	Framework internationally integrated, allows severity grading, associates with outcomes	Requires screening before use, needs objective assessment of muscle mass, need longer time	Use for formal diagnosis and decision‐making in nutritional support as part of multidisciplinary care (EASL, BSG), aligns with ESPEN, can use routine HCC CT/MRI scans for muscle mass assessment. If +: initiate nutrition support.

Abbreviations: AASLD, American Association for the Study of Liver Diseases; BMI, body mass index; BSG, British Society of Gastroenterology; CT, computed tomography; EASL, European Association for the Study of the Liver; ESPEN, European Society for Clinical Nutrition and Metabolism; GLIM, Global Leadership Initiative on Malnutrition; HCC, hepatocellular carcinoma; ICD, International Statistical Classification of Diseases; MNA‐SF, Mini Nutritional Assessment Short Form; MRI, magnetic resonance imaging; MUST, Malnutrition Universal Screening Tool; NICE, National Institute for Health and Care Excellence; NRS, Nutritional Risk Screening; PG‐SGA SF, Patient‐Generated Subjective Global Assessment Short Form; SGA, Subjective Global Assessment.

Accurate assessment of skeletal muscle mass is particularly critical, as sarcopenia independently predicts adverse outcomes in HCC [29]. Cross‐sectional imaging, specifically computed tomography (CT) at the third lumbar vertebra (L3), remains the gold standard for quantifying muscle mass. Gender‐specific thresholds for the transversal psoas thickness index (TPTI) have been defined in cirrhotic populations (TPTI < 14.56 mm/m for males; < 8.34 mm/m for females) [30]. While ultrasound is gaining traction as a noninvasive, accessible alternative for muscle assessment, it remains less standardized. Adjunctive modalities such as bioelectrical impedance analysis (BIA) and anthropometric measures (e.g., midarm muscle circumference) may provide additional context but are limited by fluid shifts and ascites in decompensated liver disease.

Commonly used laboratory parameters—including serum albumin, prealbumin, and C‐reactive protein (CRP)—offer limited specificity in this setting due to the confounding effects of hepatic synthetic dysfunction and systemic inflammation [31]. While hypoalbuminemia is consistently associated with poor prognosis, neither albumin nor prealbumin alone reliably reflects nutritional status in patients with HCC and cirrhosis.

Functional status assessment complements structural evaluation, with handgrip strength increasingly recognized as a practical, reproducible bedside measure correlated with muscle function and clinical outcomes [32]. Although further validation is needed specifically in HCC populations, it serves as a useful tool for both diagnosis and monitoring response to nutritional intervention.

Taken together, a comprehensive, multimodal approach—including validated screening tools, objective assessment of muscle mass, selected biochemical markers, and functional performance testing—is recommended to accurately evaluate nutritional status in HCC. Early identification and targeted intervention remain essential to improving outcomes in this vulnerable population.

3. Nutritional Management Across the HCC Treatment Spectrum

Nutritional management in HCC must be individualized and aligned with the specific treatment modality and disease stage, with an overarching goal of optimizing metabolic status, improving treatment tolerance, and preserving functional capacity [33]. Nutritional support plays a pivotal role in curative, locoregional, systemic, and palliative settings and should be integrated into multidisciplinary care pathways (Figure 2).

FIGURE 2.

Nutritional management across the HCC treatment spectrum. BCAA, branched‐chain amino acids; C, carbohydrates; E, energy intake; EN, enteral nutrition; esp, especially; GLIM, Global Leadership Initiative on Malnutrition; L, lipids; MNA‐SF, Mini Nutritional Assessment Short Form; MUST, Malnutrition Universal Screening Tool; NRS, Nutritional Risk Screening; ONS, oral nutritional supplements; P, protein; PG‐SGA SF, Patient‐Generated Subjective Global Assessment Short Form; PN, parenteral nutrition; SGA, Subjective Global Assessment; TEE, total energy expenditure.

3.1. Curative Settings (Resection, Transplant, Ablation)

Preoperative nutritional status is a critical determinant of postoperative outcomes in patients undergoing surgical resection, liver transplantation, or ablative therapies [32]. Malnutrition and sarcopenia have been independently associated with increased perioperative complications, prolonged recovery, and elevated mortality risk. [34] The American College of Gastroenterology recommends validated nutritional screening—such as the NRS‐2002—and individualized dietary intervention in the preoperative setting. Ruiz‐Margáin et al. stratified recommendations based on the BCLC stage [35], such as 25–30 kcal/kg/day for BCLC 0 and 30–40 kcal/kg/day for BCLC B‐C. Meanwhile, the European Association for the Study of the Liver (EASL) guideline of nutrition in chronic liver disease recommends at least 35 kcal/kg/day of energy intake and 1.2–1.5 g/kg/day of protein intake for nonobese patients [36]. Specifically, it recommends 30 kcal/kg/day energy with 1.2 g/kg/day protein to maintain or 35 kcal/kg/day with 1.5 g/kg/day protein to improve nutrition status preoperatively and 35 kcal/kg/day energy with 1.5 g/kg/day after the acute postoperative stage [36]. For obese individuals, the European Society for Clinical Nutrition and Metabolism (ESPEN) recommends 25 kcal/kg/day, but with an increased protein proportion of 2–2.5 g/kg/day (Table 2) [35]. Enhanced recovery protocols emphasize early oral intake, use of oral nutritional supplements, and ongoing monitoring of weight and intake to reduce postoperative complications and length of stay [37].

TABLE 2.

Macronutrient and micronutrient recommendations in HCC. [7, 8, 37, 38, 39]

BCLC stage	Energy	Carbohydrates	Proteins	Lipids	Micronutrients	Further considerations
General guideline‐based recommendations (not based on stage)	≥ 35 kcal/kg/day [36] Obese patients: [35, 36] 25 kcal/kg/day, with increased proportion of proteins	No % guidance in ESPEN/EASL/AASLD/ACG HCC/liver disease guidelines	> 1.2–1.5 g/kg/day [36] Obese patients: 2–2.5 g/kg/day [35, 36]	No % guidance in ESPEN/EASL/AASLD/ACG HCC/liver disease guidelines	Perform laboratory test for deficiency and correct Supplement vitamin D if < 20 ng/mL (target: serum vitamin D 25(OH)D > 30 ng/mL) [36] Test in jaundice and supplement vitamin K if deficient [36] Parenteral vitamin B1 in Wernicke's encephalopathy [36]
0 (very early)	25–30 kcal/kg/day [33]	45%–60% of total energy expenditure, fiber > 30 g/day	1.2 g/kg/day [33]	25%–30% of total energy expenditure [33] Prioritize omega 3‐rich foods		Avoid fasting, late evening snack recommended, optimize nutrition preoperatively [7, 36, 40]
A (early)	30–40 kcal/kg/day [33]	45%–60% of total energy expenditure, Fiber > 30 g/day, Avoid rapid glucose surge (insulin resistance risk)	1.3–1.5 g/kg/day [33]	25%–30% of total energy expenditure [33] Prioritize omega 3‐rich foods		Avoid sarcopenia, optimize nutrition for surgery/transplant [7, 40]
B (intermediate)	30–40 kcal/kg/day [33]	45%–60% of total energy expenditure Fiber >30 g/day Small frequent meals	1.3–1.5 g/kg/day [33]	25%–30% of total energy expenditure [33] Prioritize omega 3‐rich foods		Small, frequent meals—avoid fasting, consider oral nutritional supplements if intake less than requirement [40, 41]
C (advanced)	30–40 kcal/kg/day [33]	45%–60% of total energy expenditure [33], avoid hypoglycemia especially in anorexia	1.3–1.5 g/kg/day [33], up to 1.5–2.0 g/kg/day during systemic therapy/critical illness	25%–30% of total energy expenditure [33], high‐energy density, consider PUFA, MCT oils	Consider comprehensive supplementation of fat‐soluble vitamins (especially in cholestasis), water soluble vitamins (for hypermetabolism), and minerals especially when parenteral nutrition given [40]	Avoid cachexia, consider oral nutritional supplements/enteral nutrition, consider parenteral nutrition support in gastrointestinal failure [7, 40]
D (terminal)	35–45 kcal/kg/day [33] or comfort feeding	Consider patient preference—liberalize	1.3–1.5 g/kg/day if tolerated [33]	Consider patient preference—liberalize	Correct deficiencies which are symptomatic	Palliative care, focus in symptom relief and quality of life, standard polymeric formula can be given [7, 41]

Abbreviations: BCLC, Barcelona clinic liver cancer; MCT, medium‐chain triglycerides; PUFA, polyunsaturated fatty acid.

3.2. Locoregional Therapies

Patients undergoing transarterial chemoembolization (TACE), radiofrequency ablation (RFA), or selective internal radiation therapy (SIRT) frequently experience acute reductions in oral intake related to postprocedural pain, nausea, fatigue, or hepatic decompensation [38]. Early nutritional intervention is essential to maintain nutritional reserves and prevent unintended weight loss. Strategies include the use of high‐calorie oral nutritional supplements, texture‐modified diets, and proactive management of gastrointestinal side effects such as nausea, vomiting, and diarrhea, which may otherwise exacerbate malnutrition [33].

3.3. Systemic Therapies

Systemic treatments for HCC, including tyrosine kinase inhibitors and immune checkpoint inhibitors, are commonly associated with anorexia, dysgeusia, mucositis, and gastrointestinal disturbances, which collectively increase the risk of cachexia [39]. The Academy of Nutrition and Dietetics recommends early, individualized nutrition counseling alongside symptom‐targeted nutritional support. Oral nutritional supplements providing 200–300 kcal and 10–20 g protein per 100 mL may be used to sustain intake. Persistent inadequacy of oral intake should prompt escalation to enteral or parenteral nutrition [42]. Ongoing nutritional assessment throughout therapy is essential to minimize treatment‐related functional decline.

3.4. Palliative and End‐of‐Life Nutrition

In advanced HCC, the focus of care transitions toward quality of life, symptom relief, and ethically appropriate nutritional decision‐making. Nutritional interventions should be consistent with the patient's goals of care, prognosis, and preferences. Comfort‐oriented measures may include food fortification, texture modification, and oral supplements to alleviate dysphagia, anorexia, or fatigue. Enteral or parenteral nutrition may be considered selectively when benefits are expected, and burdens are minimal. In terminal stages, artificial nutrition should be avoided if it prolongs discomfort or does not contribute to meaningful clinical benefit [36, 40, 41].

Effective communication with patients and caregivers is critical to ensure informed decision‐making and realistic expectations regarding nutritional interventions. Multidisciplinary collaboration—including input from hepatologists, oncologists, dietitians, palliative care teams, and nursing staff—is essential to provide coordinated, patient‐centered nutritional care across the HCC continuum [8, 36, 40, 41].

Nutritional management in HCC is a dynamic process that must be continuously tailored to the evolving clinical trajectory, with early intervention, longitudinal reassessment, and individualized, patient‐centered care serving as foundational principles of effective nutritional support.

4. Therapeutic Nutritional Interventions in HCC

4.1. Macronutrient targets

Patients with HCC and underlying cirrhosis exhibit increased protein‐energy requirements secondary to hypermetabolism, systemic inflammation, and cancer‐associated catabolism.

Guidelines generally recommend an energy intake of > 30 kcal/kg/day and protein intake of 1.2–1.5 g/kg/day (Table 2), with higher targets warranted in individuals with sarcopenia or sustained catabolic stress. A summary of highest‐level evidence studies evaluating nutritional interventions for HCC can be seen in Table 3.

TABLE 3.

Summary of highest‐level‐of‐evidence studies evaluating nutritional interventions for HCC.

Intervention	Author; year	Study design, included studies	Study population and characteristics (n)	Outcome	Effect size [95%CI]	Interpretation and notes of concern
Oral branched‐chain amino acid supplementation	Sideris; 2023 [43]	Meta‐analysis, 16 studies	HCC patients (n = 1594)	Serum albumin, posttreatment	SMD = 0.54 [95% CI: 0.20–0.87]	BCAAs can be considered for improving nutrition in some decompensated patients, and may be beneficial in terms of prognosis, despite concerns about risk of bias in the studies included.
				Mortality rate	RR = 0.81 [95% CI: 0.65–1.02]
				AST	SMD = −0.13 [95% CI: −0.43–0.18]
	Van Dijk; 2022 [44]	Meta‐analysis, 54 studies	Chronic liver disease patients (n = 5184)	Event‐free survival	RR = 0.61 [95% CI: 0.42–0.88]; p = 0.008
				Overall survival	RR = 0.58 [95% CI 0.34–1.00]; p = 0.05
	Chen; 2015 [45]	Meta‐analysis, 11 studies	HCC patients undergoing anti‐HCC interventions (n = 974)	Serum albumin	SMD = 0.234 [95% CI: 0.033–0.435]; p = 0.022
				Ascites	RR = 0.545, [95% CI: 0.316–0.938], p = 0.029
				Edema	RR = 0.494, [95% CI: 0.257–0.952], p = 0.035
Late‐evening snack	Guo; 2018 [46]	Meta‐analysis, 14 clinical trials	Patients with cirrhosis (n = 478)	Carbohydrate oxidation	MD = 11.09, [95% CI: 8.14–14.04], p < 0.00001	Late‐evening snacks can be implemented as a low‐risk, simple, but effective method against overnight catabolism.
				Fat oxidation	MD = −10.12 [95% CI: −16.54 to −3.70], p < 0.00001
				Respiratory quotient	MD = 0.05 [95% CI: 0.04–0.05], p < 0.00001
				Serum albumin	MD = 2.98 [95% CI: 0.24–5.71], p = 0.03
				Cholinesterase	SMD = 2.61 [95% CI: 0.81–4.41], p = 0.005
				Hemoglobin	MD = 1.09 [95% CI: 0.04–2.15], p = 0.04
Late‐evening snack + BCAA	Morihara; 2012 [47]	Prospective study	Patients with cirrhosis who have undergone radiofrequency ablation for hepatocellular carcinoma (n = 30)	At 12 weeks, there were significant improvements in albumin (p = 0.040), total serum bilirubin levels (p = 0.042), and Child–Pugh score (p = 0.035) compared to morning‐BCAA and control
Perioperative immunonutrition containing omega‐3 fatty acids	Gao; 2021 [48]	Meta‐analysis, 9 RCTs	Patients undergoing hepatectomy (n = 966)	Overall postoperative infectious complications	OR = 0.53 [95% CI: 0.37–0.75]; p = 0.0003	Immunonutrition containing omega‐3 can be considered as studies suggest beneficial outcomes in terms of complications and length of stay, but again heterogeneity and risk of bias concerns should be taken into consideration.
				Incision infection	OR = 0.50 [95% CI: 0.28–0.89]; p = 0.02
				Length of hospital stay	MD = −3.80 [95% CI: −6.59 to −1.02]; p = 0.007
				Postoperative mortality	OR = 0.69 [95% CI: 0.26–1.83]; p = 0.46
Perioperative immunonutrition, enteral, containing adjunct key nutrients: glutamine, arginine, BCAAs, nucleotide, omega‐3 fatty acids, and beta carotene	Wong; 2020 [49]	Meta‐analysis, 11 RCTs	1084 patients, 43% undergoing hepatectomies and 90% for hepatocellular carcinoma with 89% Child–Pugh A	Postoperative wound infection	RR = 0.65 [95% CI: 0.43–0.96]; p = 0.03
				Hospital stays	MD = −4.97 days [95% CI: −8.23 to −1.72]; p = 0.003
Enteral/intravenous omega‐3, preoperatively initiated	Mohsen; 2023 [50]	Meta‐analysis, 13 RCTs	Patients undergoing abdominal surgery (n = 950)	Postoperative IL‐6	SMD = −0.55 [95% CI: −1.22 to 0.12]; p = 0.10
				Postoperative CRP	SMD = −0.14 [95% CI: −0.67 to 0.40]; p = 0.55
				Postoperative WBC	SMD = −0.58 [95% CI: −3.05 to 1.89]; p = 0.42
				Hospital stay	SMD = −0.50 [95% CI: −1.43 to 0.41]; p = 0.20
Anamorelin (oral ghrelin‐receptor agonist)	Taniguchi; 2023 [51]	Meta‐analysis, 7 RCTs	Patients with cancer‐related anorexia/cachexia syndrome (n = 1944)	Total body weight	MD = 1.73 [95% CI: 1.34–2.13]; p < 0.00001	Anamorelin as an appetite stimulant may benefit patients with anorexia/cachexia syndrome, but evidence for HCC specifically is limited.
				Lean body mass	MD = 1.06 [95% CI: 0.30–1.81]; p = 0.006
				Quality of life	SMD = 0.16 [95% CI: 0.04–0.27]; p = 0.006
Enteral nutrition vs. parenteral nutrition	Gao; 2015 [52]	Meta‐analysis, 9 studies	Patients with hepatocellular carcinoma, posthepatectomy (n = 677)	Mean serum total bilirubin	WMD = −4.29 μmol/L [95% CI: −5.55 to −3.03]; p < 0.001	Enteral nutrition is preferred whenever the gastrointestinal tract is still functional.
				Mean serum alanine aminotransferase	WMD = −20.51 U/L [95% CI: −34.65 to −6.37]; p = 0.004
				Mean plasma prealbumin level after nutrition	WMD = 27.56 mg/L [95% CI: 9.02–46.11]; p = 0.004
				Diarrhea and abdominal bloating	OR = 1.95 [95% CI: 1.33–3.13]; p = 0.005
				Time to flatus	WMD = −17.09 [95% CI: −22.04 to −12.13]; p < 0.001
				Average cost	WMD = −117.59 [95% CI: −133.52 to −101.65]; p < 0.0001
Exercise vs. control	Kawaguchi; 2024 [53]	Meta‐analysis, 11 RCTs	Patients with liver cirrhosis (n = 425)	Incidence of serious adverse events	RD = −0.03 [95% CI: −0.07 to 0.02]; p = n.s. (not significant)	Progressive combined resistance and aerobic exercise should be encouraged in HCC patients, as tolerated and tailored to portal hypertension risk.
Resistance‐aerobic combination exercise vs. control				Incidence of serious adverse events	RD = −0.12 [95% CI: −0.21 to −0.03]; p < 0.05
High and moderate vs. low physical activity	Lee; 2020 [54]	Meta‐analysis, 10 prospective cohort studies, 8 analyzed for this comparison	680 943 participants (in the 8 analyzed for high and moderate vs. low comparison)	Risk of liver cancer mortality	HR = 0.78 [95% CI: 0.73–0.84]; p = 0.001
Vitamin D	Keum; 2019 [55]	Meta‐analysis, 10 RCTs, 5 analyzed for cancer mortality	1591 deaths, n participants NR	Total cancer mortality	RR = 0.87 [95% CI, 0.79–0.96]; p = 0.005	Vitamin D can be considered for cancer patients.

Abbreviations: AST, aspartate aminotransferase; BCAA, branched chain amino acids; HCC, hepatocellular carcinoma; HR, hazard risk; MD, mean difference; NR, not reported; OR, odds ratio; RCT, randomized controlled trials; RD, risk difference; RR, risk ratio; SMD, standardized mean difference; WMD, weighted mean difference.

4.2. Oral Nutritional Supplements and BCAAs

Oral nutritional supplements can be considered when spontaneous dietary intake fails to meet energy and protein requirements. A review by Margain et al. recommended 0.20–0.25 g/kg BCAAs for BCLC0, 0.25 g/kg for BCLC A‐C, and standard polymeric formula for BCLC D [33].Formulations enriched with branched‐chain amino acids (BCAAs) are supported by evidence demonstrating benefits in improving posttreatment albumin levels and reducing ascites and edema in HCC patients [43, 45]. In a meta‐analysis involving chronic liver disease patients, BCAAs were even shown to benefit overall and event‐free survival, but these findings should be interpreted with caution due to the high risk of bias within the included studies [44].

4.3. Adjunct therapies: Appetite Stimulants and Omega‐3 Fatty Acids

Adjunctive therapies such as appetite stimulants or omega‐3 fatty acids may be considered in HCC, though the quality and consistency of supporting evidence remain variable. Anamorelin, an oral ghrelin‐receptor agonist, was shown to improve total body weight, lean body mass, and quality of life in cancer patients suffering from anorexia/cachexia, but this was not specific to HCC [51]. In posthepatectomy patients, evidence also supports beneficial outcomes of omega‐3 immunonutrition in terms of complications and length of stay, but again heterogeneity and risk of bias concerns should be taken into consideration [48, 49, 50].

4.4. Enteral and Parenteral Nutrition

Based on evidence showing significant improvements in mean plasma prealbumin levels, time to flatus, mean serum total bilirubin, and mean serum alanine aminotransferase, as well as considering the reduced average costs [52], enteral nutrition is the preferred modality of support for posthepatectomy patients when gastrointestinal function remains intact. Other indications for enteral support include severe malnutrition, failure to meet nutritional requirements orally, or the need for perioperative nutritional optimization. Parenteral nutrition is only reserved for cases of gastrointestinal failure or persistent intolerance to enteral feeding, with heightened vigilance for complications such as catheter‐related infections, fluid overload, and metabolic derangements—particularly in the context of decompensated cirrhosis. Given these risks, the decision to initiate parenteral support must be individualized, with nutrition therapy integrated into coordinated, multidisciplinary management [56].

4.5. Exercise and Rehabilitation

Exercise and physical rehabilitation serve as critical adjuncts to nutritional intervention in HCC, with the primary aim of mitigating sarcopenia and functional decline. When combined with adequate protein and energy intake, exercise can exert synergistic effects on skeletal muscle mass, strength, and physical performance. In a meta‐analysis involving 11 randomized controlled trials (RCTs), a combination of resistance and aerobic exercise significantly reduced the incidence of adverse events, in contrast to the nonsignificant effect of exercise alone. Early mobilization and implementation of structured exercise regimens are recommended across the HCC care continuum to enhance treatment tolerance, preserve independence, and improve overall quality of life. While Lee et al.'s study showed reduced risks of mortality with high and moderate intensity exercise compared to low intensity [54], patient tolerance and portal hypertension risk should still be considered when individualizing exercise and rehabilitation prescriptions for HCC patients.

5. Special Populations and Emerging Concepts

Contemporary nutritional management in HCC increasingly recognizes the heterogeneity of underlying etiologies and emphasizes disease‐specific metabolic disturbances alongside emerging precision nutrition approaches. In NASH‐related HCC, insulin resistance is a key pathophysiological driver, promoting hepatic steatosis, inflammation, and carcinogenesis [57]. Nutritional strategies in this context focus on reducing intake of simple carbohydrates and saturated fats, while promoting unsaturated fats and dietary fiber. Current guidelines endorse Mediterranean‐style dietary patterns to improve insulin sensitivity, reduce hepatic fat accumulation, and mitigate HCC risk [58]. The quality of dietary fat is particularly relevant—saturated and trans fats exacerbate steatosis and inflammation, whereas omega‐3 polyunsaturated fatty acids may exert hepatoprotective and anti‐inflammatory effects [50].

In alcohol‐related liver disease (ALD), micronutrient deficiencies—particularly thiamine and folate—are common due to inadequate intake, malabsorption, and increased metabolic demands [59]. Thiamine supplementation may be beneficial in acute settings to prevent Wernicke's encephalopathy, while folate repletion addresses macrocytic anemia. Sustained alcohol abstinence remains the cornerstone of management and significantly reduces HCC risk.

The gut microbiota is increasingly recognized as a modifiable factor in HCC pathogenesis, particularly in the setting of NASH [60]. Dysbiosis and altered microbial metabolites, including short‐chain fatty acids and bile acids, contribute to hepatic inflammation and tumorigenesis [61]. Diets rich in fiber and plant‐based components have been shown to support microbial diversity, reduce systemic inflammation, and may enhance response to immunotherapy in HCC [62, 63].

Precision nutrition represents a developing frontier, integrating data from genomics, metabolomics, and microbiome profiling to tailor dietary interventions to individual metabolic and genetic profiles [64, 65, 66]. Early studies suggest that such personalized approaches may improve metabolic regulation and potentially modify HCC risk; clinical application remains investigational and requires further validation in prospective trials.

6. Research Gaps and Future Directions

Significant gaps remain in nutrition and HCC, particularly regarding patient stratification, micronutrient guidance, intervention targets, standardization, and safety in nutritional management. Evidence by patient stratification plays a great role in individualizing nutritional therapy, but there are currently limited rigorous studies that define nutritional needs based on stage, frailty, clinical presentation, and etiology of HCC. As shown in previous sections, for some interventions such as appetite stimulants or late‐evening snacks, existing studies even involved general oncology patients with cachexia or cirrhotic patients, without specifically focusing on the HCC population. Some of the current nutritional treatments are extrapolated from non‐HCC studies, and a one‐size‐fits‐all nutritional therapy would not be sufficient as factors including liver function, malabsorption, treatment adverse effects, and many others would have a significant impact on the effectiveness and prognosis of the patients. [46] This is particularly true given the limited research supporting most micronutrient thresholds, leading current guidelines to favor symptom‐based deficiency correction over standardized daily intake recommendations for different HCC stages. [7, 45] Outcome targets such as treatment completion, body composition measures, decompensation, and quality of life have also yet to be standardized in current guidelines. Further studies using rigorous methodologies are needed to address existing gaps. In addition, recent technological developments may support the implementation and monitoring of nutrition therapy for HCC patients, including the use of tele‐nutrition methods. The future of nutritional intervention in HCC should eventually include precision medicine approaches that combine metabolomic and microbiomic data that can allow for individualized nutrition therapy, with outcomes monitored more precisely through new technological tools.

7. Conclusions

Nutrition serves as a critical focus for intervention in HCC, significantly influencing both the development and progression of the disease. Comprehensive screening and nutritional assessment in HCC are imperative and can be effectively conducted using a range of validated tools. Looking ahead, advancements in technology, metabolomics, and microbiome research present opportunities to enhance HCC nutrition care pathways through the integration of novel strategies.

Conflicts of Interest

The authors declare no conflicts of interest.

Dirjayanto, V. , Yiu, D. , Chen, R. , and Fan, K. (2026) Nutrition in Hepatocellular Carcinoma: Pathophysiological Insights, Impact, and Implications for Clinical Practice. Journal of Gastroenterology and Hepatology, 41: 78–95. 10.1111/jgh.70186.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.