Nutritional Deficiencies in Hepatorenal Syndrome Secondary to Liver Cirrhosis

Kumar B et al | DOI: 10.65188/nurexus.1037

Page 19

Journal of MedVerse Research & Practice

ISSN: 3107-4278

Nutritional Deficiencies in Hepatorenal Syndrome Secondary to Liver

Cirrhosis

Dr. Bala Kumar

, Dr. Priyanga M

Associate Professor, Assistant Professor

Department of Gastroenterology, Salem Government Medical College and Hospital

Email: balakumar86@gmail.com

Submission Date: 23.07.2025

Accepted Date: 20.08.2025

Published Date: 31.08.2025

DOI: 10.65188/nurexus.1037

article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits

unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Abstract

Malnutrition represents a frequent and clinically significant complication in patients with liver cirrhosis, and its

impact becomes more profound when hepatorenal syndrome develops. This narrative review aims to examine the

intricate association between nutritional deficiencies, cirrhosis, and hepatorenal syndrome, emphasizing contributing

mechanisms, clinical consequences, and implications for patient care. Evidence indicates that malnutrition is highly

prevalent in cirrhotic individuals, especially in those progressing to hepatorenal syndrome. Distinct features include

sarcopenia, protein-energy wasting, and deficiencies of essential micronutrients. These alterations compromise

immune competence, increase vulnerability to infections, and negatively influence hepatic and renal function.

Furthermore, systemic inflammation associated with cirrhosis and renal dysfunction accelerates catabolic activity,

thereby aggravating malnutrition. Such nutritional impairments are closely linked with reduced tolerance to

therapeutic interventions, heightened complication rates, and increased mortality. Although targeted nutritional

interventions in hepatorenal syndrome remain challenging, early recognition and proactive management of

malnutrition are vital to optimize outcomes. Integrating nutritional support into standard care may improve survival

and quality of life in this high-risk population.

Keywords: Liver cirrhosis, Hepatorenal syndrome, Malnutrition, Sarcopenia, Nutritional support, Micronutrient

deficiency, Patient outcomes

Introduction

Cirrhosis is not only associated with progressive hepatic dysfunction but also with profound nutritional

disturbances that negatively influence overall prognosis. One of the most serious complications in this

setting is hepatorenal syndrome (HRS), a unique form of renal impairment that develops in patients with

advanced liver disease and is strongly linked to increased morbidity and mortality [1]. The reported

incidence of HRS among cirrhotic patients varies widely, ranging between 0.7% and 17.5%, with an

estimated prevalence of 7% to 45% in different populations [2,3]. HRS is more frequently observed in men

than in women and is particularly common in individuals with advanced stages of cirrhosis [4]. Its

occurrence is often associated with ascites and is notably higher in hospitalized patients, especially those

admitted to intensive or critical care units [5]. The underlying pathogenesis of HRS is multifactorial and not

yet fully understood. It is generally attributed to a complex interplay of hepatocellular dysfunction,

systemic and intrahepatic inflammation, portal hypertension, and alterations in neurohormonal systems

such as the renin–angiotensin–aldosterone axis [6,7]. Clinically, HRS is classified into two forms: Type 1

HRS, which is acute, severe, and rapidly progressive, and Type 2 HRS, which presents more gradually with

a chronic course.

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Diagnosis of HRS is based on characteristic clinical and biochemical criteria. These include the presence of

ascites, a serum creatinine concentration exceeding 2 mg/dL, and the absence of alternative causes of acute

kidney injury [8]. Laboratory features often supporting the diagnosis are elevated serum bilirubin (> 2

mg/dL), persistently high serum creatinine (> 2 mg/dL), and very low urinary sodium concentrations (< 10

mmol/L) [9,10]. Importantly, diagnosis requires the careful exclusion of other etiologies of renal

impairment while confirming these specific markers.

Risk factors predisposing to HRS include advanced age, bacterial infections, and the presence of refractory

ascites. The prognosis of HRS remains extremely poor, with mortality rates approaching 80% in untreated

cases. Among fatal outcomes, sepsis is the leading contributor, followed by cardiovascular complications

and end-stage hepatic failure [11].

Pathophysiology

The development of hepatorenal syndrome (HRS) reflects a complex interaction between circulatory

disturbances, hepatic dysfunction, and systemic inflammation. The hallmark mechanism is severe renal

vasoconstriction occurring in the background of marked splanchnic and systemic arterial vasodilation,

which together result in profound renal hypoperfusion [12]. Portal hypertension plays a central role in

initiating these hemodynamic changes. Increased intrahepatic resistance leads to splanchnic vasodilation

mediated by nitric oxide, carbon monoxide, and other vasodilatory substances. This causes a reduction in

effective arterial blood volume, which in turn activates compensatory neurohormonal mechanisms,

including the renin–angiotensin–aldosterone system (RAAS), sympathetic nervous system, and vasopressin

secretion [13]. These systems attempt to preserve circulatory integrity but result in progressive renal

vasoconstriction and sodium retention.

Concurrently, systemic and intrahepatic inflammation contribute significantly to disease progression.

Bacterial translocation from the gut and recurrent infections stimulate pro-inflammatory cytokine release

(e.g., TNF-α, IL-6), worsening endothelial dysfunction and amplifying circulatory derangements [14]. This

inflammatory milieu further enhances renal vasoconstriction while impairing cardiac function, a

phenomenon described as cirrhotic cardiomyopathy, which reduces renal perfusion [15]. HRS is clinically

categorized into two main subtypes. Type 1 HRS is characterized by a rapid and severe decline in renal

function, often precipitated by infections such as spontaneous bacterial peritonitis, with serum creatinine

levels doubling to >2.5 mg/dL within two weeks. In contrast, Type 2 HRS evolves more gradually,

presenting with moderate but persistent renal impairment and refractory ascites [16].

Additionally, disturbances in renal tubular function are observed, such as impaired sodium excretion and

low urinary sodium levels, even though the renal parenchyma is structurally normal. This functional nature

of renal failure in HRS underscores why kidney histology usually appears preserved, despite severe renal

dysfunction [17]. In summary, the pathophysiology of HRS involves a cascade of portal hypertension,

systemic vasodilation, neurohormonal activation, and inflammatory pathways, ultimately culminating in

renal hypoperfusion and failure. These mechanisms explain both the clinical spectrum and the poor

prognosis associated with this condition.

Clinical Features

The clinical presentation of hepatorenal syndrome (HRS) is often subtle in its early stages and usually

occurs in the setting of advanced cirrhosis with portal hypertension and ascites. Patients frequently have a

background of progressive liver failure, which complicates the recognition of renal dysfunction, as many

symptoms overlap with those of decompensated cirrhosis [18]. The most common manifestations include

progressive oliguria, rising serum creatinine, and low urinary sodium excretion (<10 mmol/L), despite

preserved renal parenchymal structure [19]. Ascites is almost universally present and often refractory to

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diuretic therapy, serving as a hallmark of type 2 HRS. In type 1 HRS, acute kidney injury progresses

rapidly, frequently following an identifiable trigger such as spontaneous bacterial peritonitis, large-volume

paracentesis without albumin replacement, gastrointestinal bleeding, or systemic infections [20].

Clinically, patients may also exhibit features of systemic circulatory dysfunction, including hypotension,

tachycardia, and signs of poor peripheral perfusion. Laboratory abnormalities often include hyponatremia,

low urine output, and elevated blood urea nitrogen (BUN) relative to creatinine, which reflect both

impaired renal perfusion and neurohormonal activation [21]. Because structural kidney disease is absent,

urine analysis is typically bland, with no significant proteinuria or hematuria. Renal ultrasound usually

shows normal morphology, which helps differentiate HRS from other causes of renal failure in cirrhosis

such as acute tubular necrosis, glomerulonephritis, or drug-induced nephropathy [22]. An important aspect

of clinical presentation is the coexistence of malnutrition and sarcopenia, which further worsens fatigue,

muscle weakness, and immune dysfunction. These features, though often under-recognized, significantly

contribute to the poor prognosis associated with HRS in cirrhotic patients [23].

Malnutrition in Cirrhosis and Hepatorenal Syndrome

Malnutrition is one of the most frequent and serious complications of chronic liver disease, particularly in

patients with cirrhosis complicated by HRS. Studies suggest that between 50–90% of cirrhotic patients

experience some degree of nutritional impairment, which worsens with disease progression [24]. In the

setting of HRS, the burden of malnutrition is even greater due to combined metabolic, hormonal, and

inflammatory disturbances.

Mechanisms of Malnutrition in Cirrhosis with HRS

The development of malnutrition in HRS is multifactorial:

1. Reduced Nutrient Intake – Loss of appetite, altered taste sensation, nausea, and early satiety due to

ascites significantly reduce dietary intake. Hospitalized patients with fluid restrictions and frequent

paracentesis are particularly vulnerable [25].

2. Altered Metabolism – Cirrhosis induces a hypermetabolic and catabolic state, where glycogen stores are

rapidly depleted and muscle protein is broken down to maintain glucose homeostasis. This process

accelerates sarcopenia, a hallmark of malnutrition in liver disease [26].

3. Malabsorption and Maldigestion – Portal hypertension leads to edema of the intestinal mucosa, bacterial

overgrowth, and impaired bile salt circulation, all of which interfere with nutrient absorption, especially

fats and fat-soluble vitamins [27].

4. Neurohormonal and Inflammatory Activation – In HRS, systemic inflammation, activation of the renin–

angiotensin–aldosterone system (RAAS), and high circulating cytokines further disrupt protein metabolism

and contribute to muscle wasting [28].

5. Frequent Infections – Recurrent bacterial peritonitis and sepsis, common in cirrhotic patients with HRS,

enhance catabolic drive, suppress appetite, and increase energy expenditure [29].

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Figure 1: Mechanisms of Malnutrition in Cirrhosis

Clinical Impact of Malnutrition in HRS

Malnutrition and sarcopenia worsen the already poor prognosis of HRS. Patients with cirrhosis and

malnutrition have:

•Higher risk of mortality independent of liver disease severity scores.

•Reduced tolerance to infections and invasive procedures due to impaired immunity.

•Poorer response to therapies, including vasoconstrictors and albumin infusion.

•Increased hospital stays and costs, with higher rates of readmission.

•Worsened quality of life, as muscle weakness and fatigue limit daily activity [30].

In fact, malnutrition is now considered an independent predictor of survival in cirrhosis with renal

dysfunction. Early identification and nutritional support, therefore, play a crucial role in the management of

HRS [31].

Assessment of Malnutrition in Cirrhosis and Hepatorenal Syndrome

Accurate identification of malnutrition is essential in cirrhotic patients, particularly those complicated by

hepatorenal syndrome (HRS), since underdiagnosis can delay critical interventions. Traditional methods of

nutritional assessment are often unreliable in cirrhosis because of fluid overload, ascites, and peripheral

edema, which obscure true body weight and anthropometric indices [32]. Therefore, a multimodal

assessment strategy is recommended.

1. Clinical Tools

Subjective Global Assessment (SGA): Widely used for bedside evaluation; incorporates dietary history,

weight changes, gastrointestinal symptoms, and physical signs such as muscle and fat wasting. In cirrhosis,

modified SGA tools improve accuracy by adjusting for ascites and edema [33]. Royal Free Hospital Global

Assessment (RFH-GA): Specifically designed for cirrhotic patients, integrating clinical judgment with

objective measures [34].

2. Anthropometric Measures

Mid-Arm Muscle Circumference (MUAC) and Triceps Skinfold Thickness (TSF): Provide estimates of

muscle and fat reserves, though values may be skewed in fluid retention. Handgrip Strength (HGS): A

practical, reproducible marker of muscle function and sarcopenia; reduced grip strength is strongly

associated with mortality in cirrhosis [35].

3. Imaging-Based Assessments

Computed Tomography (CT) or MRI-based Muscle Analysis: Measurement of psoas or skeletal muscle

area at the L3 vertebra is considered the gold standard for diagnosing sarcopenia. CT is particularly

valuable in transplant candidates, where malnutrition strongly impacts outcomes [36]. Ultrasound Muscle

Thickness: Emerging as a non-invasive bedside alternative for assessing muscle mass.

4. Biochemical and Functional Parameters

Serum Albumin and Prealbumin: Although influenced by hepatic synthetic function and inflammation, low

levels often correlate with poor nutritional status [37]. Micronutrient Levels: Deficiencies in zinc,

magnesium, selenium, vitamin D, and fat-soluble vitamins are frequent in cirrhosis with HRS [38]. Phase

Angle (Bioelectrical Impedance Analysis – BIA): Reflects cellular integrity and body composition; reduced

phase angle predicts adverse outcomes [39].

5. Composite Scores and Guidelines

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Recent consensus guidelines recommend integrating functional measures (HGS, CT muscle analysis) with

clinical assessments (SGA, RFH-GA) to improve diagnostic accuracy. The European Society for Clinical

Nutrition and Metabolism (ESPEN) emphasizes early screening at diagnosis of cirrhosis and repeated

monitoring during decompensations such as HRS [40].

Pathophysiology of Hepatorenal Syndrome and Nutritional Implications

Hepatorenal syndrome (HRS) represents a functional renal failure in advanced cirrhosis, arising from

profound circulatory disturbances. The syndrome is primarily characterized by intense renal

vasoconstriction and systemic circulatory dysfunction, but nutritional depletion significantly influences its

progression and outcomes.

1. Splanchnic Vasodilation and Renal Hypoperfusion

Portal hypertension leads to splanchnic arterial vasodilation, resulting in reduced effective circulating

volume. This triggers activation of the renin–angiotensin–aldosterone system (RAAS), sympathetic nervous

system, and vasopressin release, collectively causing renal vasoconstriction and sodium–water retention

[41]. In malnourished patients, diminished protein stores exacerbate hypoalbuminemia, further lowering

oncotic pressure and worsening circulatory collapse.

2. Inflammation and Immune Dysregulation

Cirrhosis is a pro-inflammatory state, amplified during HRS by bacterial translocation, endotoxemia, and

systemic inflammatory mediators [42]. Malnutrition, particularly protein-calorie deficiency and

micronutrient deficits (zinc, selenium, vitamins A and D), impairs immune competence, heightening

susceptibility to infections. Infections are well-established precipitants of HRS, linking malnutrition

directly to renal deterioration.

3. Sarcopenia and Muscle Catabolism

Loss of skeletal muscle mass (sarcopenia) is a hallmark of malnutrition in cirrhosis. Muscle tissue normally

acts as an ammonia detoxification site via glutamine synthesis; sarcopenia reduces this capacity, worsening

hepatic encephalopathy and systemic inflammation [43]. The hypercatabolic state of HRS accelerates

muscle breakdown, perpetuating a vicious cycle of malnutrition and disease progression.

4. Mitochondrial Dysfunction and Energy Imbalance

HRS is associated with impaired mitochondrial function in renal tubular cells and hepatocytes, limiting

ATP production [44]. Malnutrition further contributes through inadequate energy and substrate supply,

compromising cellular repair, and aggravating multi-organ dysfunction.

5. Oxidative Stress and Micronutrient Deficiencies

Oxidative stress plays a central role in hepatocellular and renal injury. Deficiencies of antioxidants such as

vitamins C, E, and trace elements (selenium, zinc) reduce defense mechanisms, enhancing oxidative

damage in HRS patients [45].

6. Neurohormonal Overactivation and Malnutrition

Persistent RAAS and sympathetic activation lead to catabolic stress, increased protein breakdown, and

altered energy metabolism. Malnutrition worsens these adaptive responses, accelerating renal impairment

and worsening prognosis [46].

Nutritional Management and Interventions in Hepatorenal Syndrome

Nutritional optimization is a cornerstone in managing patients with cirrhosis complicated by HRS, as

malnutrition and sarcopenia are strong predictors of morbidity and mortality. The goals of nutritional

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therapy are to preserve lean body mass, optimize hepatic and renal function, prevent complications, and

improve overall survival.

1. Energy Requirements

Patients with cirrhosis and HRS have a hypermetabolic state with increased resting energy expenditure.

Current guidelines recommend an intake of 30–35 kcal/kg/day to meet energy demands and prevent

catabolism [47]. Caloric needs should be adjusted according to the patient’s clinical status, physical

activity, and degree of malnutrition.

2. Protein Intake

Contrary to older practices of protein restriction, evidence supports adequate protein intake (1.2–1.5

g/kg/day) to counteract sarcopenia and protein-energy malnutrition [48]. In cases of severe sarcopenia,

intake may be increased up to 1.8 g/kg/day, provided there is no overt hepatic encephalopathy. For patients

with recurrent encephalopathy, branched-chain amino acid (BCAA) supplementation is preferred as it

improves nitrogen balance and reduces neurocognitive complications [49].

3. Meal Pattern and Timing: Frequent small meals and a late-night carbohydrate-rich snack are

recommended to minimize fasting-induced catabolism and preserve glycogen reserves [50]. This strategy

helps maintain nitrogen balance and prevents muscle protein breakdown.

4. Micronutrient Supplementation

Cirrhotic patients, particularly those with HRS, commonly present with zinc, selenium, magnesium,

vitamin D, vitamin A, and folate deficiencies [51]. Supplementation should be individualized based on

laboratory monitoring. Zinc is crucial for ammonia detoxification, while vitamin D deficiency worsens

bone disease and muscle weakness.

5. Sodium and Fluid Management

HRS patients often require strict sodium restriction (≤2 g/day) to control ascites and edema. Fluid intake is

usually adjusted according to serum sodium and renal function. Overly restrictive diets, however, should be

avoided as they may further worsen caloric and protein intake [52].

6. Enteral and Parenteral Nutrition

Enteral nutrition is preferred whenever feasible, as it preserves gut integrity, reduces bacterial translocation,

and supports immune function. In advanced cases where oral/enteral feeding is not possible, parenteral

nutrition may be considered, with careful monitoring of electrolytes and glucose [53].

7. Specialized Nutritional Approaches

BCAA-enriched formulations: beneficial in cirrhotic sarcopenia and encephalopathy. Probiotics and

prebiotics: may help reduce bacterial translocation and systemic inflammation. Omega-3 fatty acids:

emerging evidence suggests anti-inflammatory and hepatoprotective effects [54].

8. Integration with Medical Therapy

Nutritional therapy should complement pharmacological interventions (albumin infusion, vasoconstrictors

such as terlipressin, midodrine, octreotide) and procedural approaches (TIPS, liver transplantation).

Optimizing nutritional status improves transplant eligibility, reduces post-operative complications, and

enhances recovery [55].

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Discussion

Malnutrition in cirrhotic patients with hepatorenal syndrome (HRS) represents a major clinical challenge.

The complex interaction between hepatic dysfunction, renal impairment, systemic inflammation, and

altered metabolism accelerates muscle wasting and nutrient deficiencies. Several studies have consistently

demonstrated that malnutrition and sarcopenia are independent predictors of mortality in cirrhosis,

irrespective of the Model for End-Stage Liver Disease (MELD) score, as reported by Montano-Loza et al.

[56].

The pathophysiology of malnutrition in HRS is multifactorial. Reduced oral intake due to anorexia, nausea,

and dietary restrictions is compounded by impaired digestion and absorption resulting from portal

hypertension–related gut changes. Hypermetabolism, increased protein catabolism, and hormonal

disturbances further contribute to progressive muscle breakdown, as described by Tsien et al. [57].

Additionally, ascites and fluid retention may obscure true weight loss, leading to underestimation of

nutritional deterioration, as emphasized in the ESPEN guidelines by Plauth et al. [58].

Nutritional assessment tools such as the Subjective Global Assessment (SGA), handgrip strength, mid-arm

muscle circumference (MUAC), and bioelectrical impedance analysis are increasingly utilized in clinical

practice to identify early nutritional decline. The usefulness of handgrip strength and SGA in cirrhotic

patients has been demonstrated by Alvares-da-Silva et al. [59]. Importantly, sarcopenia is now recognized

as a critical determinant of liver transplant outcomes, with malnourished patients experiencing higher

perioperative morbidity and reduced post-transplant survival, as reported by Praktiknjo et al. [60].

Recent evidence also highlights the therapeutic role of targeted nutritional interventions. Supplementation

with branched-chain amino acids (BCAAs), omega-3 fatty acids, and late-night carbohydrate intake has

been shown to attenuate muscle breakdown and improve energy homeostasis, as demonstrated by Honda et

al. [61]. Furthermore, correction of micronutrient deficiencies—including zinc, vitamin D, and selenium—

has been associated with reduced hepatic encephalopathy, lower infection rates, and improved frailty

indices, as described by Carey et al. [62].

Despite advances in the pharmacological management of HRS, including albumin infusion, vasoconstrictor

therapy, and transjugular intrahepatic portosystemic shunt (TIPS), nutritional optimization remains

underrecognized and underutilized in routine clinical practice. An integrated, multidisciplinary approach

involving hepatologists, nephrologists, dietitians, and transplant teams is essential to improve clinical

outcomes in this vulnerable population, as emphasized by Merli et al. [63].

Summary

Hepatorenal syndrome (HRS) is a severe, life-threatening complication of advanced cirrhosis, characterized

by functional renal failure due to intense renal vasoconstriction, systemic vasodilation, and neurohormonal

dysregulation. It commonly occurs in patients with ascites and carries a very poor prognosis, with mortality

rates reaching up to 80% without treatment. Type 1 HRS presents acutely and progresses rapidly, while

Type 2 evolves slowly with refractory ascites. The pathogenesis involves portal hypertension, activation of

the renin–angiotensin–aldosterone system, systemic inflammation, and circulatory collapse, leading to renal

hypoperfusion despite structurally normal kidneys.

Malnutrition is highly prevalent in cirrhotic patients, affecting 50–90%, and is particularly severe in those

with HRS. Factors contributing to malnutrition include reduced intake, malabsorption, hypermetabolism,

hormonal and inflammatory imbalances, and frequent infections. Malnutrition worsens outcomes by

reducing treatment response, increasing infection risk, prolonging hospitalization, and elevating mortality.

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Assessment tools like the Subjective Global Assessment, handgrip strength, mid-arm muscle

circumference, and imaging-based sarcopenia evaluation are crucial for early detection.

Nutritional management is a cornerstone of HRS care. Adequate energy intake (30–35 kcal/kg/day) and

protein (1.2–1.5 g/kg/day) are essential, along with BCAA supplementation, frequent small meals, and late-

night snacks to prevent catabolism. Micronutrient correction (zinc, vitamin D, selenium), sodium

restriction, and preference for enteral over parenteral nutrition improve outcomes. Integrating nutritional

therapy with medical treatments such as albumin infusion, vasoconstrictors, and TIPS can enhance

transplant readiness, reduce complications, and improve survival. A multidisciplinary approach involving

hepatology, nephrology, and nutrition teams is vital for optimal patient management.

Conclusion

Malnutrition is a critical but modifiable factor in patients with liver cirrhosis complicated by hepatorenal

syndrome. It accelerates disease progression, worsens quality of life, and adversely impacts survival and

transplant outcomes. Timely recognition of malnutrition through structured assessments, coupled with

individualized nutritional interventions—adequate calories, optimal protein intake, micronutrient repletion,

and specialized supplements—can substantially improve prognosis.

Future research should focus on integrating precision nutrition strategies with conventional HRS therapies,

thereby offering a holistic approach to management. Until then, clinicians should prioritize nutritional care

as an essential component of the therapeutic algorithm for HRS, rather than a supportive measure..

Conflict of Interest: Nil

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