TO ASSESS THE ROLE OF ALBUMIN INFUSION ON QUALITY OF LIFE IN

PATIENTS WITH HEPATOCELLULAR CARCINOMA - A PROSPECTIVE

STUDY

DISSERTATION

SUBMITTED TO THE OSMANIA UNIVERSITY, HYDERABAD IN PARTIAL

FULFILLMENT OF THE REQUIREMENT FOR THE AWARD OF THE DEGREE
OF

DOCTOR OF PHARMACY
SUBMITTED BY
Pharm. D V year students

FAZILA SHAKEEL AHMED 170120882009

SANIYA KHATOON 170120882020
ZEBA NUREEN 170120882019

IFATH FATIMA 170120882006

CLINICAL GUIDE
Dr. ANAND V KULKARNI
MD, DM HEPATOLOGY
Senior Consultant – Hepatology and Liver Transplantation.
AIG HOSPITAL, GACHIBOWLI

INSTITUTIONAL GUIDE
Dr. A. Lalitha Devi, M. Pharm, Ph.D
Associate Professor
Department of Pharmacology
[Link] Reddy College of Pharmacy, Mehdipatnam

G. PULLA REDDY COLLEGE OF PHARMACY HYDERABAD – 500028 (TS)

AUGUST 2025
 DECLARATION

We, Ms. Fazila Shakeel Ahmed, Ms. Saniya Khatoon, Ms. Zeba Nureen, Ms. Ifath Fatima,
Students of Pharm. D bearing the H.T No. 170120882009, 170120882020, 170120882019, and
170120882006 respectively, Department of Pharmacy Practice, G. Pulla Reddy College of
Pharmacy, Osmania University, Hyderabad hereby declare that the work embodied in this
dissertation entitled “TO ASSESS THE ROLE OF ALBUMIN INFUSION ON QUALITY
OF LIFE IN PATIENTS WITH HEPATOCELLULAR CARCINOMA”, is submitted to
Osmania University for the partial fulfilment of the requirements for the award of degree of
Doctor of Pharmacy under Faculty of Pharmacy is the original research work carried out by us
under the guidance and supervision Dr. A. Lalitha devi, Assoc. Prof. Department of
Pharmacology, G. Pulla Reddy College of Pharmacy.
Further we hereby declare and inform that the contents presented in this thesis has not been
submitted by me for the award of any other degree or diploma of this or any other University.

Place:

Date:

FAZILA SHAKEEL AHMED

SANIYA KHATOON

ZEBA NUREEN

IFATH FATIMA
 CERTIFICATE

This is to certify that the dissertation entitled “To assess the role of Albumin infusion on
Quality of life in patients with Hepatocellular Carcinoma”, is submitted to Osmania
University for the partial fulfillment of requirements for the award of degree of Doctor of
Pharmacy under Faculty of Pharmacy embodies the results and studies of a bonafide
research work of Ms. Fazila Shakeel Ahmed, Saniya Khatoon, Zeba Nureen, Ifath
Fatima, under the supervision of Dr. A Lalitha Devi, at G. Pulla Reddy College of
Pharmacy and the contents of the thesis do not form the basis for the award of any other
degree or diploma to the candidates from this or any other university elsewhere.

Dr. A. Lalitha Devi

Associate Professor
Department of Pharmacology
G. Pulla Reddy College of Pharmacy
Hyderabad
 CERTIFICATE

This is to certify that the dissertation entitled “To assess the role of Albumin infusion on
Quality of life in patients with Hepatocellular Carcinoma”, is submitted to Osmania
University for the partial fulfillment of requirements for the award of degree of Doctor of
Pharmacy under Faculty of Pharmacy embodies the results and studies of a bonafide
research work of Ms. Fazila Shakeel Ahmed, Saniya Khatoon, Zeba Nureen, Ifath
Fatima, under the supervision of Dr. A Lalitha Devi, at G. Pulla Reddy College of
Pharmacy and the contents of the thesis do not form the basis for the award of any other
degree or diploma to the candidates from this or any other university elsewhere.

Prof. Dr. B. Madhava Reddy

Principal
G. Pulla Reddy College of Pharmacy
Hyderabad
DEDICATED TO MY
BELOVED FAMILY
MEMBERS,
TEACHER’S AMD
FRIENDS
 TABLE OF CONTENTS
ACKNOWLEDGEMENTS I-II
LIST OF ABBREVIATIONS III
LIST OF TABLES V
LIST OF FIGURES VI
ABSTRACT VII

CHAPTER TITLE PAGE

NO. NUMBER
CHAPTER 1
1.1 HEPATOCELLULAR CARCINOMA 1
1.1.1 EPIDEMIOLOGY 1
1.1.2 ETIOLOGY AND RISK FACTORS 2-5
1.1.3 PATHOGENESIS 5-6
1.1.4 STAGES OF LIVER CANCER 7-8
1.1.5 CLINICAL PRESENTATION 8-9
1.1.6 DIAGNOSIS 10-16
1.1.7 TREATMENT 17-22
1.1.8 PREVENTION AND SURVEILLANCE 23-24
1.2 ROLE OF ALBUMIN IN LIVER DISEASE
1.2.1 ALBUMIN: STRUCTURE AND FUNCTION 24-29
1.2.2 INDICATIONS FOR ALBUMIN INFUSION IN 29-31
HEPATIC DISORDERS
1.2.3 HYPOALBUMINEMIA IN LIVER CIRRHOSIS 31-33
AND HCC
1.2.4 EVIDENCE AND GUIDELINES ON ALBUMIN 33-35
USE
1.3 QUALITY OF LIFE(QoL)
1.3.1 CONCEPT OF QoL IN CANCER 35-36
1.3.2 IMPORTANCE OF MEASURING QoL 37-39
1.3.3 EORTC-QLQ-HCC-18 39-42
CHAPTER 2
2.1 LITERATURE REVIEW 43-49
CHAPTER 3
3.1 AIM OF THE STUDY 50
3.2 OBJECTIVES 50
3.3 RATIONALE OF THE STUDY 50
CHAPTER 4
4.1 STUDY DESIGNS 51
4.2 STUDY LOCATION 51
4.3 STUDY DURATION 51
4.4 ELIGIBILITY CRITERIA 51
4.5 STUDY SELECTION 51
4.6 SOURCE OF DATA 51
4.7 SAMPLE SIZE 51
4.8 DATA COLLECTION 52
4.9 DATA ANALYSIS 52
4.10 PLAN OF WORK 53
4.11 APPROVAL OF INSTITUTIONAL ETHICS 53
COMMITTEE
CHAPTER 5
5.1 RESULTS AND DISCUSSION 54
5.2 AGE 55
5.3 GENDER 56
5.4 BMI 57
5.5 ETIOLOGY 58
5.6 COMORBIDITIES 59
5.7 CLINICAL SCORING SYSTEM 60
5.8 LABORATORY AND BIOCHEMICAL 61
PARAMETERS
5.9 QUALITY AND OUTCOME MEASURE 62
5.10 SURVIVAL 63
CONCLUSION 81
REFERENCES 82-86
 APPENDIX
INSTITUTIONAL ETHICAL COMMITTEE 87-88
DATA COLLECTION FORM 89-90
Informed Consent Forms (English) 91-99
EORTC-QLQ HCC-18 100
CO-CURRRICULAR ACTIVITIES 101-108
 ACKNOWLEDGEMENTS

First and foremost, we express our deepest gratitude to our parents and family members,
whose unwavering support, blessings, and encouragement have instilled in us the courage,
strength, and determination to pursue our goals and strive for excellence.

We wish to express our sincere thanks to Prof. Dr. B. Madahava Reddy, Principal, G.
Pulla Reddy College of Pharmacy, for providing us with the best possible facilities to carry
out our work successfully.

We are profoundly grateful to our supervisor, Dr. A. Lalitha Devi, Assoc. Prof. Department
of Pharmacology, G. Pulla Reddy College of Pharmacy, for her invaluable guidance,
constant encouragement, and patience throughout our Pharm.D studies and research. Her
unwavering support, insightful feedback, and trust in our abilities have been instrumental in
the successful completion of our thesis.

Our heartfelt thanks to our clinical guide, Dr. Anand V. Kulkarni, Senior Consultant-
Hepatology and Liver Transplantation, Asian Institute of Gastroenterology, Hyderabad,
for providing us with the opportunity to learn under her guidance and for her kind
cooperation and mentorship during the study period.

We express our gratitude to Dr. Santhosh Reddy, Manager, Clinical Pharmacy Services
and Head of Clinical Pharmacy Department, AIG Hospitals, Gachibowli, for facilitating
our research by providing the necessary resources and support within the hospital.

We also wish to thank all the staff of the Hepatology department and the non-clinical
staff of AIG hospital, Hyderabad, for the selfless service they have offered throughout the
study.

It is our privilege to express our profound gratitude to Prof. S. Srinu Naik, Chairman, BOS,
Pharm.D, Osmania University, Hyderabad; Prof. Ch. Sailu, Head, Department of Pharmacy,
University College of Technology; Prof. V. Ramesh Kumar, former Dean; and Prof. V.V.
Basava Rao, Dean, Faculty of Pharmacy, Osmania University, for their administrative and
academic support, which has been vital to the fulfilment of our postgraduate degree
requirements at Osmania University.

We also thank Mr. P. Chandrashekar, Librarian, G. Pulla Reddy College of Pharmacy,

for his valuable assistance in bringing our project to a successful completion.

Finally, we wish to extend our sincere appreciation to all the teaching, non-teaching, and
technical staff of G. Pulla Reddy College of Pharmacy for their support and cooperation,
which greatly contributed to the successful completion of our dissertation.

FAZILA SHAKEEL AHMED

SANIYA KHATOON

ZEBA NUREEN

IFATH FATHIMA
 LIST OF ABBREVIATIONS
ABBREVIATED FORM FULL FORM
AASLD American Association for the Study of Liver Diseases
ADH Alcohol Dehydrogenase
AFP Alpha-Fetoprotein
AKI Acute Kidney Injury
ALBI Albumin-Bilirubin
AMPK Activated Protein Kinase
ATZ Atezolizumab
BCLC Barcelona Clinic Liver Cancer
BVZ Bevacizumab
CAR-T Chimeric Antigen Receptor T-cell therapy
CT Computed Tomography
CYS-34 Cysteine 34
DEB-TACE Drug-eluting beads transarterial chemoembolization
DNA Deoxyribonucleic acid
ECOG Eastern Cooperative Oncology Group Performance
Status
EORTC European Organisation for Research and Treatment of
Cancer
FDA Food and Drug Administration
FDG-PET Fluorodeoxyglucose Positron Emission Tomography
FGFR Fibroblast Growth Factor Receptor
GLOBOCAN Global Cancer Observatory
HBV Hepatitis B Virus
HCC Hepatocellular Carcinoma
HCV Hepatitis C Virus
HDV Hepatitis D Virus
HE Hepatic Encephalopathy
HGDN High-Grade Dysplastic Nodule
HIV Human Immunodeficiency Virus
HNA-1 Human non-Mercaptoalbumin-1
 HNA-2 Human non-Mercaptoalbumin-2
HRQOL Health-Related Quality of Life
HRS Hepatorenal Syndrome
IGF Insulin-like Growth Factor
INCRNA long non-coding RNA
JAK/STAT Janus kinase/signal transducer and activator of
transcription
LGDN low-grade dysplastic nodules
LI-RADS The Liver Imaging Reporting and Data System
LT Liver Transplantation
MAPK/ERK Mitogen-Activated Protein Kinase/Extracellular Signal-
Regulated Kinase
MASLD Metabolic Dysfunction-Associated Steatotic Liver
Disease
MELD Model for End-Stage Liver Disease
MILS Manual In-line Stabilization
MRI Magnetic Resonance Imaging
MWA Microwave Ablation
NAFLD Non-alcoholic fatty liver disease
NF-κB Nuclear Factor kappa light chain enhancer of activated
B cells
NITS Non-invasive tests
NSAIDS Non-Steroidal Anti-Inflammatory Drugs
OS Overall Survival
PALBI Platelet-Albumin-Bilirubin
PD-1 Programmed Cell Death Protein 1
PD-LI (possibly PD-L1?) Programmed Death-Ligand 1
PDGFR-α Platelet-derived growth factor receptor alpha
PI3K/AKT Phosphoinositide 3-kinase (PI3K) / Protein Kinase B
(AKT) signaling pathway
PPARα Peroxisome Proliferator-Activated Receptor alpha
PICD Paracentesis-Induced Circulatory Dysfunction
PNPLA3 Patatin-like phospholipase domain-containing protein 3
 PROMS Patient-Reported Outcome Measures
PROS Patient-Reported Outcome
QOL Quality of Life
RET Rearranged during Transfection gene
RNA Ribonucleic Acid
ROS Review of Systems
SBP Spontaneous Bacterial Peritonitis
SIRT Selective Internal Radiation Therapy
TACE Transarterial Chemoembolization
TARE Transarterial Radioembolization
TKI Tyrosine Kinase Inhibitor
TLRS Toll-like receptors
TM6SF2 Transmembrane 6 Superfamily Member 2
TNF-α Tumor Necrosis Factor-alpha
TP53 Tumor protein p53
VCAM-1 Vascular Cell Adhesion Molecule 1
VEGF Vascular Endothelial Growth Factor
WNT/β-catenin Wingless-related integration site which involves the
protein β-catenin
 LIST OF TABLES

TABLE PAGE
TITLE OF THE TABLE
NO. NUMBER
1. Key Molecular pathways involved in HCC 6-7
2. BCLC Staging System 8
3. Liver Imaging Reporting and Data System (LI-RADS) 11-13
4. Child-Pugh Scoring System 14
5. ECOG Performance Status Scale 16-17
6. Treatment Overview 17-18
7. Current established indications for albumin use in patients 30
with cirrhosis
8. Impact of Hypoalbuminemia in Cirrhosis and HCC 33
9. Importance of Albumin in HCC 35
10. Core Dimensions of Quality of Life and Their Impact on 37
Cancer Patients
11. HCC-18 Score range 41
12. Plan of work 53
13. Distribution of subjects based on age group 55
14. Distribution of subjects based on Gender 56
15. Distribution of subjects based on BMI 57
16. Distribution of subjects based on Etiology 58
17. Distribution of subjects based on comorbidities 59
18. Distribution of subjects based on child-Pugh score 60
19. Distribution of subjects based on ALBI 61
20. Distribution of subjects based on MELD score range 62
21. Distribution of subjects based on Systemic Therapy 63
22. Distribution of subjects based on Albumin therapy status 64
23. Distribution of subjects based on Ascites 65
24. Distribution of subjects based on Haemoglobin levels 66
25. Distribution of subjects based on TLC levels 67
26. Distribution of subjects based on Albumin levels 68
27. Distribution of subjects based Total Bilirubin levels 69
28. Distribution of subjects based on ALT Levels 70
29. Distribution of subjects based on AST Levels 71
30. Distribution of subjects based on Creatinine Levels 72
31. Distribution of subjects based on INR Levels 73
32. Distribution of subjects based on Sodium Levels 74
33. Distribution of subjects based on AFP Levels 75
34. Distribution of subjects based on Quality of Life 76
35. Distribution of subjects based on the incidence of 77
Hyponatremia
36. Distribution of subjects based on Ascites Control 78
37. Comparative analysis of survival outcomes 79-80
 LIST OF FIGURES

FIGURE PAGE
TITLE OF THE FIGURES
NO. NUMBERS
1. Liver showing hepatocellular carcinoma (HCC) lesion 1
2. Pathogenic mechanisms and risk factors contributing to 3
hepatocarcinogenesis
3. Mechanisms of pathogenesis of hepatocellular carcinoma 5
(HCC)
4. Jaundice (scleral and dermal icterus) 9
5. Ascites 9
6. Magnetic Resonance Imaging (MRI) of HCC 10
7. Contrast-Enhanced CT scan Showing Hepatocellular 11
Carcinoma
8. A framework for the diagnosis and staging of patients with 13
HCC
9. Radiofrequency Ablation 20
10. Microwave Ablation 20
11. Flow chart on Treatment strategies in the management of 21
HCC
12. Activity of atezolizumab and bevacizumab in the cancer– 21
immunity cycle, indicating potential additive or synergistic
antitumor effects
13. Effect of Lenvatinib on the tumour immune 23
microenvironment
14. From Risk to Remission: A Visual Guide to HCC Prevention 24
and Surveillance
15. Human Serum Albumin structure and binding sites 25
16. Flowchart on Albumin functions 27
17. Albumin synthesis, distribution, and metabolism 28
18. Flow chart on Anti-inflammatory properties of albumin 29
19. Flowchart on Overview of Albumin’s Role in Liver Disease 31
Progression
20. Mechanism underlying the contribution 32
of hypoalbuminemia to ascites formation in liver cirrhosis
21. Flow chart on Multifaceted Role of Albumin in 34
Hepatocellular Carcinoma
22. Flow chart on the Model of factors involved in the health- 36
related quality of life
23. The impact of HCC and its treatments on patient well-being 39
24. Flow chart on Sample selection 54
25. Bar graph showing the distribution of subjects based on age 55
26. Pie chart showing the distribution of subjects based on 56
gender
27. Pie chart showing the distribution of subjects based on BMI 57
28. Horizontal Bar Chart showing Distribution of Subjects by 58
Etiology
29. Bar graph showing distribution of subjects by comorbidities 59
30. Pie chart showing distribution of subjects by Child-Pugh 60
score
31. Line graph showing distribution of subjects based on ALBI 61
grade
32. Bar graph showing distribution of subjects based on MELD 62
score
33. Pie chart showing distribution of subjects based on Systemic 63
Therapy
34. Pie chart showing distribution of subjects based on Albumin 64
therapy status
35. Pie chart showing distribution of subjects based on Ascites 65
36. Bar graph showing distribution of subjects based on 66
Haemoglobin levels
37. Bar graph showing distribution of subjects based on TLC 67
levels
38. Bar graph showing distribution of subjects based on 68
Albumin levels
39. Bar graph showing distribution of subjects based on Total 69
Bilirubin levels
40. Bar graph showing distribution of subjects based on Total 70
Bilirubin levels
41. Line graph showing distribution of subjects based on AST 71
levels
42. Line graph showing distribution of subjects based on AST 72
levels
43. Line and Bar graph showing distribution of subjects based 73
on INR levels
44. Bar graph showing distribution of subjects based on Sodium 74
levels
45. Bar graph showing distribution of subjects based on AFP 75
levels
46. Bar graph showing distribution of subjects based on Quality 76
of Life
47. Bar graph showing distribution of subjects based on the 77
incidence of Hyponatremia
48. Donut chart illustrating ascites control 78
49. Kaplan–Meier plot illustrating survival outcomes 79
ABSTRACT
 ABSTRACT

Background:
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally,
frequently arising in patients with underlying liver cirrhosis and hypoalbuminemia. Albumin
infusion is often used to manage complications such as ascites and hypoalbuminemia-related
symptoms, but its influence on quality of life (QoL) and other clinical outcomes remains
uncertain.

Aim:
To assess the role of albumin infusion on quality of life in patients with hepatocellular
carcinoma.

Methods:
A prospective observational study was carried out on 50 patients diagnosed with hepatocellular
carcinoma, who were evenly divided into two groups based on whether they received albumin
infusion (25 in the albumin group and 25 in the non-albumin group). Detailed demographic
profiles, clinical parameters, comorbidities, and liver disease severity—assessed using Child-
Pugh, MELD, and ALBI scores—were documented. Laboratory and clinical data were
collected at three time points: baseline, first follow-up, and second follow-up. Statistical
comparisons were performed to assess changes over time and differences between groups,
while survival outcomes were analyzed using the Kaplan–Meier method.

Results:
The albumin group had more advanced liver disease at baseline, reflected by higher MELD
scores (median 12.4 vs 9.12) and a greater proportion of ALBI Grade 3 patients. While serum
albumin levels slightly improved in the albumin group, the changes were not statistically
significant. Creatinine and INR remained stable in the albumin group but worsened in the non-
albumin group, suggesting a renal and coagulation protective trend with albumin.
A significant decline in AST levels was observed only in the albumin group (p = 0.01), while
AFP levels showed a marked reduction in both groups, but more sharply in the albumin group
(p < 0.001). The albumin group also showed significantly improved quality of life scores over
time (p = 0.006), despite starting with poorer QoL at baseline. Though more patients in the
albumin group developed hyponatremia, this was not statistically significant. Ascites control
was better in the albumin group (64% vs 52%). Survival analysis demonstrated longer median
survival in the albumin group (15.3 months vs 9.6 months), though not statistically significant
(Log-rank p = 0.936). The survival curve suggested that albumin may delay mortality events
during early follow-up.

Conclusion:
This prospective observational study suggests that albumin infusion in hepatocellular
carcinoma patients may offer supportive clinical benefits, particularly in stabilizing renal and
coagulation parameters, improving quality of life, and enhancing ascites control. Although no
statistically significant survival benefit was observed, the trend toward delayed mortality in the
albumin group highlights its potential as an adjunctive therapy in selected patients with
advanced liver dysfunction. Further large-scale studies are warranted to validate these findings.
CHAPTER-1 INTRODUCTION

1. INTRODUCTION
1.1 HEPATOCELLULAR CARCINOMA
Hepatocellular carcinoma (HCC) is a malignant neoplasm that arises from hepatocytes,
the primary functional cells of the liver (Figure 1). Representing approximately 90% of all
primary liver cancers, HCC is differentiated from other hepatic tumors by its cellular origin
and characteristic clinical, radiological, and pathological traits. It stands as the most
prevalent primary liver cancer in adults and ranks among the leading causes of cancer-
related deaths globally.
HCC predominantly develops in individuals with
preexisting liver conditions such as cirrhosis or
chronic hepatitis. Often presenting as a single tumor,
early-stage HCC is typically asymptomatic. Patients
usually exhibit symptoms related to their underlying
liver disease, including ascites and jaundice. In more
Figure 1: Liver showing hepatocellular
advanced stages, HCC may present with vague
carcinoma (HCC) lesion.
symptoms such as abdominal discomfort, unintended
weight loss, and reduced appetite.
1.1.1 EPIDEMIOLOGY
Hepatocellular carcinoma (HCC) accounts for 80–90% of primary liver cancers globally.
According to GLOBOCAN 2020, HCC is the sixth most commonly diagnosed cancer
and the third leading cause of cancer-related deaths worldwide. Its incidence shows
distinct regional differences:
 Highest rates are seen in East and Southeast Asia and sub-Saharan Africa, largely due
to hepatitis B virus (HBV).
 In Western countries, risk factors like alcohol-related liver disease, hepatitis C virus
(HCV), and metabolic dysfunction-associated steatotic liver disease (MASLD) are
predominant.
 Peak age of onset:
 Asia and Africa: 30–50 years
 Western nations: 70–75 years
 Gender disparity: Males are more frequently affected (M:F ratio = 2:1 to 4:1).
India, being part of Southeast Asia, reflects many of the regional epidemiological features.
However, recent trends show distinct national shifts in disease etiology and burden:

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CHAPTER-1 INTRODUCTION

 Incidence: 2.15 per 100,000

 Prevalence: 2.27 per 100,000
 Mortality: 2.21 per 100,000

Historically, HBV was the leading cause of HCC. Now, alcohol use and MASLD are
emerging as major etiological factors.
 Males still have a higher incidence, but the rate of rise is faster in females.
 Northeastern states have the highest burden, but western states like Gujarat,
Maharashtra, Goa, and Kerala are new hotspots with rapid increases.
 This reflects changing lifestyles, increased alcohol consumption, and rising rates of
obesity and diabetes.
1.1.2 ETIOLOGY AND RISK FACTORS
o Liver cirrhosis: 80% of cases
o Additional risk factors
 Chronic hepatitis B or C virus infection
 Alcohol-associated liver disease
 Metabolic dysfunction-associated steatotic liver disease (MASLD)
 Hemochromatosis

 Wilson disease
 Alpha-1 antitrypsin deficiency
 Hepatic autoimmune diseases (e.g., autoimmune hepatitis)
 Schistosomiasis

 Glycogen storage disease

 Chronic ingestion of food contaminated with aflatoxin
-Aflatoxin is a carcinogen produced by Aspergillus flavus
-Results in G: C → T: A transversion in codon 249 of the TP53 gene leading to an
inactivating mutation
 Aflatoxins are considered one of the most potent carcinogens.

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CHAPTER-1 INTRODUCTION

Figure 2: Pathogenic mechanisms and risk factors contributing to hepatocarcinogenesis.

CHRONIC VIRAL HEPATITIS (HBV, HCV, HDV, HIV):

Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are well-
established risk factors for hepatocellular carcinoma (HCC). HBV has been associated
with HCC for thousands of years and is responsible for 75–80% of virus-related HCC
cases, infecting over 240 million people globally. As a partially double-stranded DNA
virus, HBV can integrate into the host genome, inactivating tumor suppressor genes like
p53, triggering oxidative stress, and activating oncogenic pathways (e.g., PI3K/Akt,
STAT3, Wnt/β-catenin), thereby promoting both cirrhotic and non-cirrhotic HCC.
In contrast, HCV is a single-stranded RNA virus that does not integrate into the host
genome. Instead, HCV proteins (both structural and non-structural) directly interfere with
host cellular processes such as transcription, cytokine production, lipid metabolism, and
hepatocyte growth regulation. Chronic HCV infection leads to persistent inflammation,
oxidative and endoplasmic reticulum (ER) stress, and epigenetic changes (via miRNA
and lncRNA modulation), ultimately driving fibrosis and cirrhosis. Though it accounts
for a smaller proportion of virus-related HCC (10–20%), HCV has a higher propensity

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CHAPTER-1 INTRODUCTION

to cause chronic infection and cirrhosis compared to HBV. It also promotes angiogenesis
and metastasis, accelerating malignant transformation.
Other viral co-infections, including hepatitis D virus (HDV) and human
immunodeficiency virus (HIV), may further modulate HCC risk, especially in
individuals with pre-existing HBV or HCV infections.

From NAFLD to MASLD:

In 2023, the NAFLD Nomenclature Consensus Group introduced the term metabolic
dysfunction-associated steatotic liver disease (MASLD) to replace NAFLD. MASLD
is defined by hepatic steatosis combined with at least one cardiometabolic risk factor and
has become the leading cause of chronic liver disease, particularly in Asia. It significantly
contributes to hepatic fibrosis, increasing the risk of hepatocellular carcinoma (HCC) and
related mortality.
Non-invasive tests (NITs), commonly used for assessing fibrosis and steatosis in
NAFLD, have been shown to be equally effective for MASLD. Studies in Asian
populations revealed a 99% overlap between NAFLD and MASLD diagnoses, with
similar fibrosis prevalence and NIT results, indicating comparable disease
characteristics.
Recent epidemiological data demonstrate a decline in viral hepatitis-related HCC deaths,
while MASLD-associated HCC mortality is rising rapidly, now ranking as the third
leading cause of HCC deaths and projected to become the second by 2032.
These findings highlight the growing importance of MASLD as a major etiological factor
in HCC development. Understanding MASLD’s role in hepatic fibrosis and
carcinogenesis is crucial for improving diagnosis, risk stratification, and preventive
strategies.

AFLD:
Arises from chronic excessive alcohol intake and is a major cause of hepatic steatosis,
inflammation, fibrosis, and progression to HCC. Ethanol is metabolized primarily via
ADH and CYP2E1, generating acetaldehyde and reactive oxygen species (ROS), which
induce DNA damage, oxidative stress, and chronic inflammation.
Factors influencing susceptibility include female sex (due to lower ADH activity and
estrogen effects), ethnicity, and genetic variants (e.g., PNPLA3, TM6SF2, CYP2E1

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CHAPTER-1 INTRODUCTION

polymorphisms). Alcohol impairs lipid metabolism (↑DNL, ↓PPARα), alters gut

permeability (↑endotoxin), and activates Kupffer cells, promoting hepatic injury.
AFLD often coexists with diabetes and viral hepatitis, enhancing hepatocarcinogenic
risk. Compared to NAFLD, AFLD is associated with greater inflammatory cell
infiltration and faster progression to cirrhosis and HCC.

AFLATOXINS
Aflatoxins are toxic metabolites produced by Aspergillus species, commonly
contaminating staple foods such as maize and peanuts in tropical and subtropical regions.
Chronic dietary exposure to aflatoxins, particularly aflatoxin B1, is a well-established
risk factor for hepatocellular carcinoma. Aflatoxin B1 induces DNA mutations,
especially in the tumor suppressor gene TP53, leading to genomic instability and
promoting carcinogenesis. The synergistic effect of aflatoxin exposure with chronic
hepatitis B virus (HBV) infection significantly increases the risk of HCC development.
Despite improvements in food safety, aflatoxin exposure remains a critical public health
concern in many low- and middle-income countries, where it contributes substantially to
the global burden of liver cancer.

1.1.3 PATHOGENESIS

Figure 3: Mechanisms of pathogenesis of hepatocellular carcinoma (HCC).

In pathway (A), a liver that appears morphologically normal undergoes chronic
exposure to pro-cirrhotic agents such as hepatitis B virus (HBV), hepatitis C virus
(HCV), alcohol, and aflatoxins. This persistent exposure leads to the development of

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CHAPTER-1 INTRODUCTION

cirrhosis, where ongoing inflammation fosters the formation of low-grade dysplastic

nodules (LGDN). These nodules can then advance to high-grade dysplastic nodules
(HGDN). The altered cellular environment and immune responses within the cirrhotic
liver promote the accumulation of both driver and passenger mutations, ultimately
resulting in the onset of overt hepatocellular carcinoma (HCC).
Pathway (B) represents an alternative, increasingly common route to HCC through fatty
liver disease. As this condition progresses, it generates elevated oxidative stress, which
contributes to cirrhosis. Similar to pathway (A), chronic inflammation in the cirrhotic
liver environment drives the progression from LGDN to HGDN and eventually to HCC,
driven by comparable changes in the immune and cellular milieu.

Pathway Main functions in HCC Key Effects

IGF signalling Drives cell growth and Enhances cell proliferation,
metabolism, especially in insulin- blocks apoptosis, and promotes
resistant HCC blood vessel formation
Wnt/β-catenin Regulates liver cell development Increase proliferation, invasion,
and tissue regeneration survival, and fibrosis through
gene activation
JAK/STAT Mediates inflammation and Amplifies chronic inflammation,
immune responses in the liver leading to cancer progression
PI3K/AKT Controls cell survival, growth, and Supports tumor cell growth and
metabolism survival, worsening insulin
resistance
MAPK (including Responds to stress signals, Contributes to inflammation,
JNK) promotes inflammation, and cell fibrosis, and liver cell injury
death
AMPK Senses cellular energy status, Inhibits fibrosis and cancer by
regulates metabolism controlling energy balance and
cell growth
NF-κB & TLR Central to inflammatory signalling Promotes the secretion of
and immune activation inflammatory cytokines, leading
to liver damage and fibrosis

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p53 Regulates cell cycle, DNA repair, Excess activation leads to

and apoptosis inflammation, fat buildup, cell
death, and cancer risk

Table 1: Key Molecular pathways involved in HCC

Hepatocellular carcinoma (HCC) development is a complex process involving multiple

molecular signaling pathways that regulate cellular proliferation, survival, inflammation,
and fibrosis. Among these, the Insulin-like Growth Factor (IGF) signaling pathway plays
a crucial role by promoting tumor cell growth and angiogenesis, especially in conditions
of insulin resistance.
The Wnt/β-catenin pathway is frequently dysregulated in HCC and contributes to
increased proliferation and invasiveness of cancer cells, as well as promoting fibrotic
changes in the liver microenvironment. Similarly, the JAK/STAT signaling cascade
mediates inflammatory responses that can enhance tumor progression in chronically
inflamed liver tissue.
The PI3K/AKT pathway is involved in supporting tumor cell survival and metabolism,
while the MAPK pathway, including the JNK sub-pathway, responds to cellular stress
and promotes inflammatory and fibrotic responses that contribute to liver injury.
Energy sensing by AMPK acts as a tumor suppressor by inhibiting fibrosis and
uncontrolled cell growth. Meanwhile, inflammatory pathways regulated by NF-κB and
Toll-like receptors (TLRs) drive the secretion of pro-inflammatory cytokines,
exacerbating liver damage and fibrosis.
Lastly, the tumor suppressor p53 gene regulates DNA repair and apoptosis. However, its
dysfunction or overactivation in chronic liver disease can paradoxically promote
inflammation, lipid accumulation, and cancer development.
Together, these pathways create a pro-tumorigenic environment that supports the
initiation and progression of HCC.

1.1.4 STAGES OF LIVER CANCER

The American Association for the Study of Liver Diseases (AASLD) recommends the
Barcelona Clinic Liver Cancer staging system (BCLC), which requires an assessment of
the following factors:
 Tumor burden
 Assessment of local extension: Multiphase CT or MRI abdomen

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 Assessment for metastatic disease: FDG-PET OR CT chest, abdomen, and pelvis

with bone scintigraphy
 Liver function, determined by the Child-Pugh score
 Eastern Cooperative Oncology Group (ECOG) performance status

BARCELONA CLINIC LIVER CANCER (BCLC) STAGING SYSTEM

BCLC STAGE CRITERIA

Very early hepatocellular  Single tumor ≤ 2 cm

carcinoma (Stage 0)  Child–Pugh A
 ECOG PS 0–1
Early-stage hepatocellular  Single tumor > 2 cm or 2 to 3 tumors ≤
carcinoma (Stage A) 3 cm
 Child–Pugh A or B
 ECOG PS 0–1
Intermediate stage hepatocellular  > 3 tumors OR 2–3 tumors, any > 3
carcinoma (Stage B) cm in size
 Child–Pugh A or B
 ECOG PS 0–1
Advanced stage hepatocellular  Portal vein invasion
carcinoma (Stage C)  Or Nodal or extrahepatic metastasis
 Child–Pugh A or B
 ECOG PS 0–2
End-stage hepatocellular  Child–Pugh C
carcinoma (Stage D)  Or ECOG PS > 2

Table 2: BCLC Staging System

1.1.5 CLINICAL PRESENTATION

Patients with hepatocellular carcinoma (HCC) often do not show symptoms initially,
and the onset of symptoms usually indicates advanced disease. However, some patients
with underlying chronic liver disease may present symptoms early. Approximately 90–
95% of HCC cases exhibit a classic triad of symptoms:
 Pain in the right upper quadrant of the abdomen,

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 A palpable mass,
 Weight loss.
Other common symptoms include:
 Jaundice,
 Hepatic encephalopathy,
 Generalized swelling (anasarca),
 Fluid accumulation in the abdomen (ascites),
 Bleeding from varices,
 Diarrhea,
Skin manifestations associated with HCC include:
 Pityriasis rotunda,
 The leser-trélat sign (the sudden appearance of multiple seborrheic keratoses),
 Dermatomyositis,
 And pemphigus foliaceus.
Additionally, Porphyria Cutanea Tarda has been connected with HCC patients who have
chronic hepatitis C infection.

Figure 4: Jaundice Figure 5: Ascites

(scleral and dermal
icterus)

1.1.6 DIAGNOSIS
Initial diagnostics
 Ultrasound abdomen (preferred initial imaging modality in most cases)
 Consider serum AFP levels to increase the detection rate.

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Perform further imaging (typically multiphase imaging, e.g., CT or MRI abdomen) if

the following are detected:
 Lesion ≥10 mm
 Lesion of any size and AFP (if performed) ≥ 20 ng/mL

Perform a liver biopsy in the following cases:

 Inconclusive multiphase imaging
 Liver lesions suspicious for HCC in patients without cirrhosis

Laboratory studies: to evaluate liver function and assess for underlying etiologies
Confirmed HCC diagnosis: Perform further studies for staging of HCC

MRI is considered the gold standard for HCC diagnosis,

offering superior sensitivity and a lower false-negative
rate compared to CT. Advances such as gadoxetate-
enhanced MRI have further improved detection rates,
particularly for lesions smaller than 2 cm, outperforming
both CT and extracellular contrast-enhanced MRI.
Figure 6: Magnetic Resonance
Conversely, extracellular contrast MRI offers slightly Imaging (MRI) of of HCC
higher specificity for small HCC lesions and is often
preferred in clinical settings such as pre-transplant evaluation.

Ultrasound is widely used due to its safety, accessibility, and affordability. However, its
diagnostic utility in HCC is limited by low sensitivity and specificity, as well as technical
challenges caused by patient factors like obesity, rib shadowing, or the presence of
chronic liver diseases such as NASH, NAFLD, and cirrhosis. While effective for
screening liver steatosis and fibrosis, ultrasound is less reliable for definitive HCC
diagnosis and staging.

CT scans provide quick and quantitative imaging with high sensitivity (93%) and
specificity (100%) for detecting liver metastases. Despite this, CT imaging can be
affected by factors such as liver iron overload and other tissue characteristics that alter
X-ray attenuation, in addition to radiation exposure concerns.

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Figure 7: Contrast-Enhanced
CT- Scan Showing
Hepatocellular Carcinoma

The Liver Imaging Reporting and Data System (LI-RADS), developed by the
American College of Radiology and endorsed by the 2018 American Association for the
Study of Liver Diseases (AASLD) guidelines, provides a standardized classification for
liver lesions on CT and MRI. LI-RADS assigns categories ranging from LR-1 (definitely
benign) to LR-5 (definitely malignant), facilitating consistent risk stratification. The
system demonstrates high sensitivity (92%) but moderate specificity (55.5%). When
combined with qualitative imaging, sensitivity improves to 97% though specificity
declines.

LI-RADS is recommended exclusively for patients with established risk factors for HCC,
such as cirrhosis or chronic hepatitis B infection, and is not intended for pediatric patients
under 18 years or for those with vascular-related liver fibrosis or congenital hepatic
disorders.

Classification Definition Imaging features

LR-NC Noncategorizable Non-diagnostic for benign or
malignant features due to
technical quality
LR-1 Definitely Benign Diagnosis for a benign entity
LR-2 Probably Benign Distinct nodules with a size of
< 20 mm and no major or
malignant features
LR-3 Intermediate Probability for Non-rim arterial phase
HCC hyperenhancement with size <
20 mm with no major features,
Arterial phase
hypoenhancement or

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isoenhancement with the

following:
 Size <20 mm and <1 major
feature
 Size >20 mm and no
malignant features
LR-4 Probably HCC Non-rim arterial phase
hyperenhancement with the
following:
 Size < 10 mm with >1
major feature
 Size 10–19 mm with
enhancing capsule and no
additional major features
 Size >20 mm with no
major features
Arterial phase
hypoenhancement or
isoenhancement with the
following:
 Size <20 mm with >2
major features
 Size >20 mm with >1
major features
LR-5 Definite HCC Non-rim arterial phase
hyperenhancement with the
following:
 Size 10–19 mm with non-
peripheral washout or
threshold growth
 Size 10–19 mm with >2
major features

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 Size >20 mm with >1

major features
LR-TIV Malignancy with Tumor in Enhancement of soft tissue in
Vein the portal vein
LR-M Probably or Definitely Targetoid mass Non-targetoid
Malignant mass with the following:
 Infiltrative
 Diffuse restriction
 Necrosis or ischemia

Table 3: Liver Imaging Reporting and Data System (LI-RADS)

Figure 8: A framework for the diagnosis and staging of patients with HCC.
BCLC, Barcelona Clinic Liver Cancer; CEUS, contrast-enhanced ultrasound; CT, computed tomography;
ECA, extracellular contrast agent; ECOG PS, Eastern Cooperative Oncology Group performance status;
HBA, hepatobiliary agent; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LI-RADS, liver
reporting and data system; MRI, magnetic resonance imaging

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BIOMARKERS OF HCC:
Alpha-fetoprotein (AFP) remains the most widely used biomarker. However, its
diagnostic performance varies with tumor size, showing a sensitivity of only ~25% for
tumors under 3 cm, and up to ~50% for those above 3 cm. AFP levels can also fluctuate
based on the degree of underlying liver damage, especially in cirrhotic patients.
Moreover, elevated AFP can be seen in other conditions such as germ cell tumors, chronic
hepatitis, and gastric cancers, limiting its diagnostic specificity.
The interpretation of AFP levels depends heavily on the threshold chosen:
 AFP >30 ng/mL offers high sensitivity but low specificity.
 AFP >2000 ng/mL provides high specificity but low sensitivity.

Des-Gamma-Carboxyprothrombin (PIVKA-II) is an abnormal form of prothrombin

produced when the vitamin K–K-dependent γ-carboxylation process is disrupted, either
due to vitamin K deficiency or, importantly, due to defects in hepatocellular carcinoma
cells themselves
EVALUATING THE PROGNOSIS:
1. Child-Pugh Score
Points Assigned
Parameter
1 2 3
Ascites Absent Slight Moderate
Bilirubin, mg/dl <2 2-3 >3
Albumin, g/dl >3.5 2.8-3.5 <2.8
Prothrombin time
Seconds over control 1-3 4-6 >6
INR <1.8 1.8-2.3 >2.3
Encephalopathy None Grade 1-2 Grade 3-4

Table 4: Child-Pugh Scoring System Grade A: < 7.0 points

Grade B: 7-9 points
Grade C: 10-15 points

The Child-Pugh score has been widely validated as a reliable predictor of

postoperative mortality, especially after portocaval shunt procedures, and is also

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used to estimate the risk associated with other major surgeries. Following abdominal
surgery, mortality rates vary significantly by Child-Pugh classification:

 Child Class A: ~10% mortality

 Child Class B: ~30% mortality
 Child Class C: ~70–80% mortality

Patients in Class A are generally suitable candidates for elective surgical procedures.
Those in Class B may undergo surgery following appropriate medical optimization,
though they still carry elevated risk. Elective surgery is typically contraindicated in
Class C patients due to the extremely high risk of complications and death.

In addition to surgical risk, the Child-Pugh score is useful in predicting overall

mortality and complications from liver failure, such as variceal bleeding. In one
study evaluating one-year outcomes, mortality rates were 0% in Class A, 20% in
Class B, and 55% in Class C.

2. MELD Score
The components of the MELD score are:
 Serum creatinine (mg/dL)
 If dialysis was performed twice in the last week, then creatinine is given a
value of 4 mg/dL
 Total bilirubin (mg/dL)
 INR
These variables are used to calculate the score with the following formula:

MELD = (0.957 x ln [Cr]) + (0.378 x ln [bilirubin]) + (1.120 x ln [INR]) + 0.643

(ln = log to the base of e, loge)

Ranges from 6 to 40, with higher numbers correlating to more severe liver
dysfunction

The implementation of the MELD score to prioritize liver transplant candidates has
reduced pre-transplant mortality among those on the waiting list. However, its use
remains controversial because the score does not reflect the potential survival benefit
that a patient may gain from undergoing a transplant.

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3. ALBI Score
The Albumin-Bilirubin (ALBI) score is a quantitative tool for evaluating liver
function in patients with hepatocellular carcinoma (HCC). It is derived from serum
albumin and bilirubin levels, and classifies liver function into three grades: Grade 1,
2, and 3
The ALBI score is calculated using the following formula:

ALBI score = (log10 bilirubin [µmol/L] × 0.66) + (albumin [g/L] × -0.085).

Grade 1: ≤ -2.60; (Best liver function)

Grade 2: -2.60 to ≤ -1.39;
Grade 3: > -1.39 (Severe Impairment)

4. ECOG
The Eastern Cooperative Oncology Group (ECOG) performance status scale ranges
from 0, indicating a patient who is fully active and unrestricted in daily activities, to
5, which denotes death. This scale is widely applied in clinical settings to assess
disease progression and the extent to which a patient’s ability to perform daily tasks
is impacted, especially in various types of cancer. Additionally, ECOG status serves
as a crucial factor in determining treatment options and estimating long-term survival
outcomes.

GRADE ECOG PERFORMANCE STATUS

0 Fully active, able to carry on all pre-disease
performance without restriction
1 Restricted in physically strenuous activity but
ambulatory and able to carry out work of a
light or sedentary nature, e.g., light housework,
office work
2 Ambulatory and capable of all self-care but
unable to carry out any work activities; up and
about more than 50% of waking hours

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3 Capable of only limited self-care; confined to

bed or chair more than 50% of waking hours
4 Completely disabled; cannot carry on any
selfcare; totally confined to bed or chair
5 Dead

Table 5: ECOG Performance Status Scale

1.1.7 TREATMENT
 Refer the patient to a specialist multidisciplinary team.
 Initiate treatment based on the stage of hepatocellular carcinoma.
 Prevent further deterioration of any associated liver disease:
 Treat underlying etiologies, e.g., antivirals for hepatitis, chelation therapy for
hemochromatosis.
 Advise alcohol abstinence
 Avoid hepatotoxic drugs.

Overview of Treatment by HCC Stage

Stage of Treatment aim Treatment
Cancer
Very early– Curative  First line
stage HCC or o Minimal
early-stage concomitant liver disease: surgical
HCC resection
o Significant
concomitant liver disease: liver
transplantation
 Alternative: ablative
therapy e.g. radiofrequency ablation
Intermediate- Neoadjuvant (curative)  Locoregional therapy with:
stage HCC OR noncurative o Transcatheter arterial
chemoembolization
o Transarterial radioembolization

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Advanced  Systemic chemotherapy

HCC o First line: targeted treatment e.g.,
with atezolizumab/bevacizumab
o Alternatives:
Noncurative -Nontargeted chemotherapy
-Hepatic arterial infusion
chemotherapy
End-stage Typically, supportive care only
HCC

Table 6: Treatment Overview

Management of hepatocellular carcinoma (HCC) is tailored based on the tumor stage

and the patient’s liver function, necessitating a multidisciplinary approach for optimal
outcomes. In early-stage disease, curative interventions such as surgical resection, liver
transplantation, and local ablative techniques (e.g., radiofrequency or microwave ablation)
offer the greatest potential for prolonged survival or complete cure.
For patients who are ineligible for surgery, locoregional therapies including Transarterial
chemoembolization (TACE), Radioembolization, and Ablation can help control tumor
progression.
In cases of advanced HCC, the landscape of systemic therapy has evolved. Multikinase
inhibitors like sorafenib and Lenvatinib, along with immune checkpoint inhibitor
combinations (e.g., atezolizumab plus bevacizumab), now constitute the first-line standard
of care. Second-line options include agents such as regorafenib, cabozantinib, and
ramucirumab.
Immunotherapy combinations have demonstrated survival advantages over traditional
treatments, though response rates may differ depending on the etiology of HCC, with viral-
related HCC showing more favorable outcomes.
Emerging therapies under investigation, such as gene therapy, CAR-T cell therapy, and
targeted molecular strategies, aim to overcome treatment resistance and enhance
effectiveness. Increasing emphasis is being placed on personalized treatment plans, guided
by tumor biology and individual patient characteristics, to optimize both survival and
quality of life.

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1. Liver Resection
 Technique: Surgical removal of the liver portion harboring the tumor; often done
laparoscopically (MILS).
 Indications: Solitary tumors, preserved liver function, absence of significant portal
hypertension.
 Recurrence Risk: High (~70% in 5 years), especially with poor tumor biology (e.g.,
vascular invasion).
 Advantages: Curative potential; minimally invasive approaches improve outcomes.
 Limitation: Not suitable in advanced cirrhosis or if the remnant liver volume is
inadequate.

2. Liver Transplantation
 Technique: Replacement of diseased liver with a donor liver; can be from living or
deceased donor.
 Indications: HCC within Milan criteria, poor liver function, or recurrence post-
resection.
 Recurrence Risk: Low (~10–15%) if strict selection criteria are followed (e.g., AFP
< 1000 ng/mL).
 Notes: LT treats both tumor and the underlying liver disease. Salvage LT is possible
after recurrence post-resection.

3. Thermal Ablation (Radiofrequency/Microwave)

 Technique: Image-guided percutaneous heating of tumors to induce necrosis.
 Indications: Tumors ≤2 cm, unsuitable for resection or LT.
 Recurrence Risk: Moderate (depends on tumor size/location).
 Notes: Minimally invasive, can be repeated, preferred over surgery in high-risk
patients.

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Figure 9: Radiofrequency Ablation Figure 10: Microwave Ablation

4. Locoregional Therapies (LRT)

A. TACE (Transarterial Chemoembolization)
 Mechanism: Delivers chemotherapy and embolic agents directly to tumor
vasculature.
 Indications: Intermediate-stage HCC, bridging/downstaging to LT.
 Recurrence Risk: Moderate to high; not curative alone.
 Types: Conventional (cTACE) and drug-eluting beads (DEB-TACE); no clear
superiority.

B. TARE/SIRT (Transarterial Radioembolization)

 Mechanism: Radioactive microspheres (e.g., Yttrium-90) target tumors via the
hepatic artery.
 Indications: Unresectable tumors, bridging to transplant, radiation lobectomy.
 Recurrence Risk: Low when used as segmentectomy (>400 Gy achieves complete

necrosis).
 Advantage: Effective in larger or centrally located tumors; better local control than

TACE.

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Flowchart 1: Treatment strategies in the management of HCC

MANAGEMENT OF ADVANCED-Stage HCC

First line: Targeted Therapy
A cancer therapy directed at a specific molecular target. The goal is to effectively attack
cancer cells while minimizing the impact on healthy cells. Targeted therapies are
usually small molecules or antibodies.

Preferred: Atezolizumab/Bevacizumab

Figure 11: Activity of atezolizumab and bevacizumab in the cancer–immunity

cycle, indicating potential additive or synergistic antitumor effects
Atezolizumab (ATZ) is an immune checkpoint inhibitor that targets PD-L1, a protein
expressed on tumor cells and tumor-infiltrating immune cells. By binding to PD-L1,

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ATZ prevents its interaction with PD-1 and B7-1 (CD80), two key inhibitory receptors
on activated T cells.
Under chronic stimulation, as seen in cancer, PD-1 is upregulated and its engagement
with PD-L1 suppresses T-cell proliferation, cytokine release, and cytotoxic function,
leading to T-cell exhaustion. Additionally, PD-L1 binding to B7-1 on T cells and
antigen-presenting cells further reduces immune activation by impairing cytokine
production and T-cell responses.
Tumor cells can exploit this mechanism by overexpressing PD-L1 to evade immune
surveillance.

Bevacizumab (BVZ) is a monoclonal antibody that binds to vascular endothelial growth

factor (VEGF), blocking its interaction with VEGF receptors (VEGFR) and thereby
inhibiting angiogenesis.
Given that hepatocellular carcinoma (HCC) is a highly vascular tumor with elevated
micro vessel density, VEGF-driven angiogenesis plays a central role in tumor growth.
Besides promoting new blood vessel formation and vascular leakage, VEGF also
suppresses anti-tumor immunity by inhibiting dendritic cell maturation, attracting
immunosuppressive cells, and upregulating immune checkpoints like PD-L1

"BVZ prepares the tumor microenvironment by removing immune barriers, while ATZ
unleashes the immune attack."

This synergistic mechanism results in:

 Better tumor shrinkage
 Longer survival
 Improved quality of life

Alternative: Levatinib / Sorafenib

Lenvatinib is a multi-targeted tyrosine kinase inhibitor (TKI) that has gained attention
as an effective treatment option for various malignancies, including hepatocellular
carcinoma (HCC).
Its therapeutic action is mediated through the inhibition of multiple receptors that play
key roles in tumor angiogenesis, cell proliferation, and immune system regulation.

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Specifically, lenvatinib targets vascular endothelial growth factor receptors (VEGFR)

1 through 3, fibroblast growth factor receptors (FGFR) 1 to 4, platelet-derived growth
factor receptor alpha (PDGFRα), as well as RET and KIT tyrosine kinases. By
concurrently blocking these signaling pathways, lenvatinib impairs critical processes
necessary for tumor growth and the development of new blood vessels.

Sorafenib: Sorafenib inhibits Raf kinase (part of the MAPK/ERK pathway), VEGFR,
and PDGFR, directly affecting pathways like Raf/MEK/ERK involved in tumor cell
proliferation and survival.

Figure 12: Effect of Lenvatinib on the tumour immune microenvironment

1.1.8 PREVENTION AND SURVEILLANCE

Hepatocellular carcinoma (HCC) prevention strategies involve several key measures,
including hepatitis B virus (HBV) vaccination, early diagnosis and management of
hepatitis C virus (HCV) infection, and lifestyle modifications—particularly weight
reduction in patients with non-alcoholic fatty liver disease (NAFLD). In areas where
aflatoxin exposure is common, efforts to reduce exposure have shown benefit. Given
alcohol's strong role in liver cancer development, complete abstinence is strongly
advised. While the evidence is still limited, avoiding or quitting smoking may also
lower the risk of HCC. Additionally, coffee consumption has been associated with a
reduced risk of HCC and is therefore encouraged.

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Individuals with cirrhosis or chronic HBV infection—regardless of cirrhosis status—

are classified as high-risk and should be enrolled in routine surveillance programs.
However, guidelines for monitoring non-cirrhotic individuals remain uncertain. The
current standard for surveillance is biannual ultrasound examinations, with or without
alpha-fetoprotein (AFP) testing. Although conclusive data on COVID-19's direct
impact on HCC surveillance are lacking, the pandemic has disrupted regular follow-up
care, and its long-term effects on HCC outcomes are likely to become more apparent in
the coming years.

Figure 13: From Risk to Remission: A Visual Guide to HCC Prevention and Surveillance

1.2 ROLE OF ALBUMIN IN LIVER DISEASE

"The role of albumin in liver disease transcends its function as a plasma expander,
encompassing crucial contributions to immune regulation, detoxification, and
maintenance of systemic homeostasis. With advancing insights into hepatic
pathophysiology, especially in conditions like cirrhosis, ascites, hepatorenal syndrome
(HRS), and spontaneous bacterial peritonitis (SBP), the clinical appreciation of albumin
has significantly broadened."

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1.2.1 Albumin: Structure and Function

Human serum albumin (HSA) is a 66.5 kDa globular protein made up of 585 amino acids.
Its heart-shaped structure consists of three homologous domains (I, II, III), each
subdivided into two subdomains (A and B) stabilized by 17 disulfide bridges. These allow
flexibility for ligand binding and maintain structural integrity.

Though non-glycosylated, HSA is rich in charged amino acids and features a single free
cysteine residue with a redox-active thiol group, enabling metal binding and antioxidant
activity. HSA binds and transports a wide range of endogenous and exogenous
substances, including hormones, fatty acids,
bilirubin, drugs, and metal ions.
Domain IB contains the unconjugated
bilirubin binding site, while subdomains IIB
and IIIB accommodate long-chain fatty acids
and bacterial endotoxins. Sudlow site I
(subdomain IIA) and site II (subdomain IIIA)
are major drug-binding sites, showing affinity
for various pharmacological agents like
warfarin and NSAIDs.
Functionally, HSA acts as a free radical Figure 14: Human Serum Albumin
scavenger, particularly through its thiol structure and binding sites
group, which exists predominantly as
mercaptoalbumin. Oxidative stress converts this to disulfide forms (HNA-1, HNA-2),
associated with aging and chronic disease. HSA also plays roles in coagulation by
transporting antithrombin and heparin cofactor II, and modulates immune responses by
dampening oxidative stress and inflammatory signaling.
Genetic variants of HSA rarely cause disease, though some forms exhibit altered thyroid
hormone or nitric oxide binding, with possible anti-apoptotic or antibacterial properties.
Functional Features of Albumin
Human serum albumin (HSA) is a multifunctional protein with a range of physiological
roles that extend beyond its well-known oncotic properties. These functions stem from
its unique structural and biochemical characteristics, including its high plasma
concentration and net negative charge.

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 Maintenance of Plasma Oncotic Pressure

Albumin is the major contributor to plasma oncotic pressure, accounting for
approximately 75% of this force. This is largely due to its abundance in the plasma
and its net negative charge, which facilitates the attraction of sodium ions and,
consequently, water molecules. Albumin constitutes more than half of all circulating
plasma proteins, reinforcing its role in volume regulation and fluid homeostasis.
 Binding, Transport, and Metabolism
Owing to its structural flexibility and charge properties, albumin can bind a wide
array of endogenous and exogenous molecules. These include drugs, hormones, fatty
acids, bilirubin, bile acids, nitric oxide, metals, anions, and bacterial toxins like
endotoxin and protein G-like albumin-binding molecules. It serves as a carrier,
depot, and regulator for many of these compounds, supporting both metabolism and
detoxification.
 Antioxidant Capacity
Albumin is a major extracellular antioxidant, largely due to the presence of its free
thiol group at Cys-34, which represents around 80% of total extracellular thiols. This
group actively neutralizes reactive oxygen and nitrogen species. Additionally,
albumin binds transition metals such as copper and iron, preventing their
participation in free radical-generating reactions. Its interaction with heme also
provides lipid antioxidant protection.
 Immunomodulatory Activity
HSA binds and neutralizes endotoxins, thereby reducing their biological activity. In
vitro findings suggest that physiological levels of albumin can mitigate endotoxin-
induced immune dysfunction. In conditions such as acute alcoholic hepatitis,
albumin may improve neutrophil function and reduce the risk of infection and organ
failure. Furthermore, studies indicate that albumin enhances cellular antioxidant
defenses, modulates inflammatory pathways such as NF-κB, and inhibits pro-
inflammatory mediators like TNF-α and VCAM-1 expression.
 Regulation of Capillary Permeability
More than half of albumin exists in the extravascular space, where it plays a critical
role in maintaining capillary barrier integrity and regulating vascular permeability.
Its interactions with the extracellular matrix contribute to vascular homeostasis.

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 Hemostatic Influence
Albumin binds nitric oxide at the Cys-34 residue, forming nitrosoalbumin (HSA-
NO). This complex may have vasodilatory properties and inhibit platelet
aggregation. Studies have linked low albumin levels (hypoalbuminemia) with
increased platelet aggregation, highlighting the role of albumin in hemostasis.
 Endothelial Stabilization
The vascular endothelium relies on a balance of factors that regulate tone,
coagulation, fibrinolysis, and barrier integrity. Albumin helps maintain this balance
by reducing inflammation and oxidative stress and by modulating neutrophil
adhesion. Evidence from both experimental and clinical studies indicates that
albumin infusion improves endothelial function, as seen in patients with spontaneous
bacterial peritonitis, where albumin therapy enhanced hemodynamic stability and
reduced markers of endothelial dysfunction compared to other volume expanders.

Oncotic
Pressure

Capillary Solubilisation,
permeability transport,
metabolism

ALBUMIN
Hemostatic FINCTIONS Antioxidant
effect

Endothelial Immunomodulation
stabilization

Flowchart 2: Albumin functions

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CHAPTER-1 INTRODUCTION

Albumin is synthesized exclusively in the liver by hepatocytes and released into the
intravascular space. From the whole-body albumin pool, 30%-40% stays in the vascular
compartment. The remaining native albumin goes to the interstitial space through the
capillary (transcapillary escape rate). Depending on the tissue involved, the mechanism
to escape from circulation may be different: by way of sinusoids (liver, bone marrow),
fenestrated endothelia (pancreas, adrenal gland), or via transcitosis. Albumin returns to
systemic circulation by way of the lymphatic system. Although albumin is known as an
extracellular molecule, it is taken up by many cell types by endocytosis such as
endothelial cells. After endocytosis, albumin can either be catabolized through lysosomal
degradation or released to the extracellular space.

Figure 15: Albumin synthesis, distribution, and metabolism.

Albumin binds various substances, including drugs, fatty acids, bilirubin, and endotoxins,
helping regulate their biological activity, distribution, and elimination. It exhibits
antioxidant effects by scavenging reactive oxygen species via its cysteine-34 residue and
by binding toxic metals. Albumin also exerts anti-inflammatory actions by suppressing
TNF-α expression both directly (through transcriptional inhibition) and indirectly (by
preserving glutathione and protecting against oxidative damage). This reduces NF-κB
activation and leukocyte recruitment, limiting inflammation.

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Flow chart 3: Anti-inflammatory properties of albumin

1.2.2 Indications for Albumin Infusion in Hepatic Disorders

Historically, human serum albumin (HSA) was utilized in cirrhotic patients for plasma
volume maintenance due to its oncotic properties. However, as understanding of fluid
balance and diuretic therapy advanced, its routine use declined. A resurgence in interest
emerged with evidence supporting its protective role against circulatory and renal
dysfunction in cirrhosis, particularly when used alongside vasoconstrictors or during
large-volume paracentesis. Albumin, when used appropriately, mitigates the progression
of renal failure and circulatory derangements in decompensated cirrhosis by restoring
effective arterial blood volume and modulating systemic inflammation and oxidative
stress.

Clinical Applications in Liver Disease

1. Management of Ascites and Paracentesis-Induced Circulatory Dysfunction
In patients undergoing large-volume paracentesis, albumin prevents post-procedural
renal impairment more effectively than synthetic colloids or crystalloids. It restores
effective circulatory volume and counters the activation of vasoconstrictor systems,
thereby preserving renal perfusion.

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2. Hepatorenal Syndrome (HRS)

HRS is a functional renal failure seen in advanced cirrhosis. Albumin, in combination
with vasoconstrictors (e.g., terlipressin), improves renal perfusion and reverses HRS
more effectively than vasoconstrictor therapy alone. Albumin enhances intravascular
volume, decreases sympathetic overactivity, and improves systemic vascular resistance.

3. Spontaneous Bacterial Peritonitis (SBP)

SBP often leads to renal dysfunction due to endotoxemia-induced circulatory collapse.
Clinical trials demonstrate that albumin co-administered with antibiotics reduces renal
impairment and mortality, highlighting its immunomodulatory and volume-expanding
benefits.

Implications in Hepatocellular Carcinoma (HCC)

In patients with cirrhosis and HCC, hypoalbuminemia serves as a negative prognostic
marker reflecting impaired hepatic synthetic function, systemic inflammation, and
malnutrition. The administration of albumin in such populations may support overall
quality of life, improve tolerance to anticancer therapies, and modulate systemic
inflammation. Moreover, the detoxification and volume-corrective functions of albumin
may mitigate complications commonly encountered in advanced HCC, such as ascites,
SBP, or paracentesis-related renal dysfunction.

CLINICAL CONDITION DOSE AND SCHEDULE OF

ADMINISTRATION
PREVENTION OF Paracentesis >5 1: mandatory 8 g/l of ascites tapped
PICD Paracentesis <51: preferred
PREVENTION OF RENAL DYSFUNCTION 1.5 g/kg bw at diagnosis + 1 g/kg
INDUCED BY SBP bw at day 3
DIAGNOSIS OF HRS-AKI 1 g/kg bw for 2 days
TREATMENT OF HRS-AKI 20-40 g/day
(associated with
vasoconstrictors)

Table 7: Current established indications for albumin use in patients with cirrhosis

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Liver disease

Albumin Infusion
Albumin synthesis

Improves oncotic pressure

Complications
+ immune function

Reduces complications
and mortality
Ascites Renal failure

Infections

Flowchart 4: Overview of Albumin’s Role in Liver Disease

Progression
1.2.3 Hypoalbuminemia in Liver Cirrhosis and Hepatocellular Carcinoma (HCC)
Hypoalbuminemia in Cirrhosis
The development of ascites in liver cirrhosis is a complex process primarily driven by
portal hypertension and the retention of sodium and water. Hypoalbuminemia, a frequent
consequence of impaired liver function, plays a significant role in this process. Reduced
albumin levels decrease plasma oncotic pressure, leading to an expansion of interstitial
fluid and a relative reduction in effective circulatory volume. This triggers compensatory
mechanisms that promote sodium and water retention, particularly through increased
antidiuretic hormone (arginine vasopressin) secretion and upregulation of renal water

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CHAPTER-1 INTRODUCTION

channels such as aquaporin 2. Interestingly, while activation of the renin-angiotensin-

aldosterone system is characteristic in cirrhosis, hypoalbuminemia-induced ascites does
not appear to alter angiotensin II or aldosterone levels significantly. Additionally,
changes in peritoneal permeability and systemic inflammation do not seem to contribute
directly to ascites related to hypoalbuminemia. These findings underscore the critical role
of hypoalbuminemia in promoting fluid retention and ascites formation in cirrhotic
patients, providing a mechanistic basis for the therapeutic use of albumin infusions in
managing ascites.

Figure 16: Mechanism underlying the contribution of hypoalbuminemia to ascites

formation in liver cirrhosis

Hypoalbuminemia in HCC
Low serum albumin levels, or hypoalbuminemia, have been identified as an important
independent predictor of tumor progression in patients with hepatocellular carcinoma
(HCC), including those with early-stage disease and low biomarker readings. Among
liver transplant candidates with HCC, albumin levels below 3.4 g/dL correlated with an
increased risk of tumor growth before transplantation, regardless of established risk
factors like tumor size, stage, or alpha-fetoprotein (AFP) levels. This prognostic

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significance was especially evident in patients classified as low-risk by standard

measures, where those with hypoalbuminemia exhibited significantly lower progression-
free survival rates at two years compared to patients with normal albumin levels. These
results indicate that assessing albumin levels can help identify HCC patients at higher
risk of disease progression, thereby informing more intensive or personalized treatment
approaches. Therefore, monitoring and managing hypoalbuminemia is vital for
improving outcomes in HCC patients, particularly those awaiting liver transplant or
undergoing curative treatments.
Hepatocellular
Parameter Cirrhosis
Carcinoma (HCC)
↓ Hepatic synthesis, ↑
Etiology of Same as cirrhosis + tumor-
catabolism, and
hypoalbuminemia associated catabolism
inflammation
Ascites, SBP, HRS, HE, Poor prognosis, ↓ tolerance
Clinical implications
circulatory dysfunction to therapy, ↑ complications
Child-Pugh score, ALBI ALBI grade, a predictor of
Prognostic value
grade therapy outcomes
May support QOL,
IV albumin improves
modulate inflammation, and
Therapeutic relevance outcomes in SBP, HRS,
reduce the risk of
and PICD
complications
Under investigation for
Long-term albumin
Emerging approaches inflammation modulation
infusion
and functional improvement

Table 8: Impact of Hypoalbuminemia in Cirrhosis and HCC

1.2.4 Evidence and Guidelines on Albumin Use

Serum albumin serves not only as a key marker of liver function but also plays critical
roles in the management, prognosis, and emerging therapies for hepatocellular carcinoma
(HCC). Numerous studies emphasize the importance of maintaining adequate serum
albumin levels in HCC patients, as hypoalbuminemia is strongly associated with poorer
outcomes.

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Role of Albumin in HCC

Prognostic Inhibits tumor Growth

Biomarker

Guidelines Risk Drug carrier for Targeted

Stratification Therapy

Used in diagnostic
Monitoring Marker
Imaging

Flow chart 6: Multifaceted Role of Albumin in Hepatocellular Carcinoma

Firstly, albumin is recognized as an independent prognostic indicator. Lower albumin

concentrations correlate with increased tumor size, greater metastatic potential, and
reduced survival rates, regardless of treatment modality. Albumin-based prognostic tools
such as the ALBI and PALBI scores are now integrated into clinical risk stratification
and staging systems, helping guide treatment decisions more precisely.
Beyond its biomarker function, albumin appears to exert direct anti-tumor effects. In vitro
and in vivo studies show that albumin suppresses hepatocellular carcinoma growth by
modulating cellular signaling pathways reducing MAP kinase activity, downregulating
cell cycle proteins, and decreasing the expression of alpha-fetoprotein (AFP), all of which
are involved in tumor proliferation and invasiveness.
Additionally, albumin is increasingly being utilized as a multifunctional nanocarrier for
targeted drug delivery and diagnostic imaging in cancer, including HCC. Its long half-
life, biocompatibility, and ability to bind hydrophobic molecules make it ideal for
transporting anticancer agents specifically to tumor tissues, thereby enhancing drug
efficacy while minimizing systemic toxicity.

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Current guidelines advocate for the regular monitoring of serum albumin levels in HCC
patients, not only to assess liver reserve but also as part of comprehensive risk evaluation.
Although albumin infusions are commonly used to treat complications like ascites and
spontaneous bacterial peritonitis in cirrhotic patients, their direct therapeutic role in
inhibiting HCC progression remains investigational and is not yet established as standard
of care

Function Description Importance in HCC

Indicator of Liver Health Shows how well the liver is Helps assess disease stage
making proteins and prognosis
Antioxidant Role Reduces harmful oxidative May slow tumor growth by
molecules lowering inflammation
Prognostic Use Part of liver function Predicts survival chances
scoring tools and treatment outcomes
Supportive Therapy Albumin infusions to Improves symptoms and
correct low levels liver-related complications
Drug Carrier Used to deliver Enhances targeting and
chemotherapy drugs reduces side effects
effectively

Table 9: Importance of Albumin in HCC

1.3 QUALITY OF LIFE (QoL) IN HCC PATIENTS

WHO defines Quality of Life as an individual's perception of their position in life, in

the context of the culture and value systems in which they live, and in relation to their
goals, expectations, standards, and concerns.
The concept of quality of life is significant across all areas of clinical practice. It holds
particular importance in specialties like hospice and palliative care, where the focus shifts
from curative treatment to aligning with patient goals and enhancing overall well-being.
Notably, research highlights that the effects of disease progression, symptoms, prognosis,
and palliative interventions on quality of life can differ considerably among individuals.

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1.3.1 Concept of QoL in cancer

Cancer is a condition characterized by the uncontrolled proliferation of cells in various
parts of the human body. Epidemiologically, it is one of the leading non-communicable
diseases and represents a major global public health concern. In clinical practice, there is
a strong emphasis on understanding how cancer and its treatments impact a patient's
quality of life (QOL), which typically refers to health-related quality of life. Every cancer
patient should be supported in achieving all aspects of QOL, including physical, mental,
social, and functional well-being. Although QOL is challenging to quantify, numerous
frameworks and validated tools are available to evaluate and promote it in individuals
with cancer. A higher QOL has been associated with increased life expectancy and
enables patients to lead more socially engaged and productive lives. Therefore,
maintaining and improving QOL should be a fundamental component of both cancer
prevention and management strategies.

Individual characteristics
Age, sex, education, cultural background, number of comorbidities, etc

Functional status Overall quality of

Symptoms General health
Physical function, perceptions life
Gastro-intestinal
psychological
symptoms, level of
function, social
energy, pain, mood etc
function,
cognitive function
etc

Flow chart 7: Model of factors involved in the health-related quality of life

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1.3.2 Importance of measuring QoL

Quality of Life (QoL) is a multidimensional concept encompassing physical, emotional,
social, and functional well-being. In cancer care, QoL has emerged as a critical outcome
measure, especially given the complex and often long-term nature of treatment and
survivorship. As advances in oncology have increased survival rates, attention has shifted
not only to prolonging life but also to improving the lived experience of patients during
and after treatment.
Cancer and its treatments can impact a patient’s ability to carry out daily activities,
maintain emotional balance, and engage in meaningful relationships. Therefore, QoL
assessments are essential for evaluating the burden of disease, tailoring supportive care,
and measuring the effectiveness of both medical and psychological interventions. It also
aids clinicians in making shared decisions with patients and improving overall treatment
satisfaction and adherence.

Cancer and its treatment can significantly impair various domains of a patient’s life.
Therefore, QoL is best understood as a composite of multiple interrelated domains:

QoL Dimension Key components

Physical Well-being Fatigue, pain, nausea, sleep,
appetite, and mobility
Psychological Well-being Anxiety, depression, fear, coping,
and body image
Social Well-being Relationships, support systems, and
social roles
Functional Well-being Ability to work, perform daily
activities

Table 10: Core Dimensions of Quality of Life and Their Impact on Cancer Patients

Importance In HCC Patients

Patients diagnosed with hepatocellular carcinoma (HCC) often experience a markedly
diminished quality of life (QoL) compared to the general population. Commonly reported
symptoms include fatigue, pain, sleep disturbances, emotional distress, and appetite loss
many of which may persist long after treatment completion. Several demographic and

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CHAPTER-1 INTRODUCTION

clinical factors, such as advanced tumor stage, concurrent cirrhosis, female sex,
unemployment, and living alone, are significantly associated with poorer QoL outcomes.
In cases of advanced or unresectable HCC, systemic therapies can introduce side effects
such as diarrhea, abdominal discomfort, and hand-foot syndrome, further impairing
patient well-being. Conversely, surgical resection—particularly through minimally
invasive techniques like laparoscopic or robotic procedures—has demonstrated potential
in improving QoL, though preoperative functional status and psychosocial variables
heavily influence long-term results.
Notably, baseline QoL is emerging as a robust, independent predictor of survival in
advanced HCC, sometimes surpassing traditional clinical parameters in prognostic
relevance. However, despite the increased focus on QoL in liver cancer care, significant
research gaps persist, particularly in understanding the spiritual domain and emotional
coping mechanisms of advanced-stage patients.
Integrating patient-reported outcome measures (PROMs) into routine oncology practice
is now widely recommended. These tools can guide individualized treatment choices and
foster a more patient-centered approach. To meaningfully enhance QoL among HCC
patients, comprehensive care must prioritize not only symptom control and medical
management but also psychological support, effective communication, and respect for
individual values and preferences.

Patient-Reported Outcomes (PROs) in Hepatocellular Carcinoma

Patient-reported outcomes (PROs) are direct self-assessments by patients regarding their
health status, collected without interpretation by clinicians or third parties. These tools
offer a more sensitive and timely evaluation of symptoms compared to clinician-reported
measures, particularly in the cancer population. In hepatocellular carcinoma (HCC),
patients frequently report symptoms such as fatigue and cognitive disturbances with
greater intensity and earlier onset than what is typically recorded by healthcare providers.
This discrepancy is especially evident in subjective symptoms, where clinician
assessments may underrepresent the actual burden experienced by the patient.
The feasibility of incorporating PROs has been well-documented in clinical research, and
regulatory authorities like the U.S. Food and Drug Administration (FDA) actively
support their use in therapeutic trials to capture patient-centered outcomes. However, the
routine use of PROs in everyday clinical practice faces barriers such as administrative

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CHAPTER-1 INTRODUCTION

demands and financial costs. Nonetheless, policy initiatives like alternative payment
models are promoting the adoption of PROs as a standard component of patient care.
In the context of HCC, PRO measures have shown promise in multiple domains. These
include aiding in shared decision-making, predicting prognosis, informing treatment
development, and tailoring palliative care strategies. Current research and pilot programs
suggest that integrating PROs into clinical workflows can significantly enhance patient-
centered care, offering clinicians a more nuanced understanding of the patient’s lived
experience.
While the use of PROs in HCC management is currently more common in research
settings, their potential to inform real-time treatment decisions and improve quality of
life is increasingly being recognized. As such, the development and validation of HCC-
specific PRO instruments are essential to advance personalized care and therapeutic
outcomes.

Figure 17: The impact of HCC and its treatments on patient well-being

1.3.3 The European Organisation for Research and Treatment of Cancer (EORTC)
Quality of Life Questionnaire [EORTC-QLQ-HCC-18]
Standard guidelines were used in the development of the EORTC QLQ-HCC18. It is
intended to be used in conjunction with the core instrument to evaluate all significant
HRQOL characteristics in HCC patients. The questionnaire's material was gathered from
a variety of sources, including the patients themselves, medical experts who treat them,
and published research. The 18 questions in the QLQ-HCC18 are thought to include two

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single-item symptom scales (sex interest and abdominal swelling), one multi-item
functional scale (body image), and five multi-item symptom scales (fatigue, jaundice,
nutrition, pain, and fever).
HCC18 index-score was defined as the sum of all 8 QLQ-HCC18 symptom/problem
scales divided by 8 (the total number of QLQ-HCC18 scales). A higher HCC18 index-
score reflects a worse overall HRQOL. This is the mathematical formula:
Scoring Methodology of the EORTC QLQ-HCC18
The European Organisation for Research and Treatment of Cancer Hepatocellular
Carcinoma-specific quality of life questionnaire (EORTC QLQ-HCC18) is a validated
tool designed to assess disease- and treatment-related symptoms in patients with
hepatocellular carcinoma (HCC). It evaluates patient-reported outcomes across eight
symptom domains relevant to HCC.
Each item in the EORTC QLQ-HCC18 is scored on a 4-point Likert scale ranging from
1 ("not at all") to 4 ("very much"). The scoring process involves the following steps:

1. Raw Score (RS):

For each domain or symptom scale, the raw score is computed as the average of the
responses to the items comprising that scale.

RS= Sum of the item scores in a domain

Number of items answered in that domain

2. Linear Transformation to 0–100 Scale:

The raw score is then linearly transformed to a standardized score ranging from 0 to 100
using the EORTC Scoring Manual method:

Standardized Score=(RS−1/range)*100

Where the range is typically 3 (i.e., maximum score of 4 minus minimum of 1).
A higher score indicates a greater symptom burden or more severe problems in that
domain.

3. HCC18 Summary Index Score:

The HCC18 summary index (or composite score) reflects the overall symptom burden.

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CHAPTER-1 INTRODUCTION

It is calculated by taking the arithmetic mean of the eight symptom domain scores,
provided that at least 50% of items in each domain are completed. The domains included
are:
o Fatigue
o Body Image
o Jaundice
o Nutrition
o Pain
o Fever
o Sexual Interest
o Abdominal Swelling

HCC18 Summary Index Score = Fatigue + Body Image + Jaundice + Nutrition + Pain +
Fever + Sexual Interest + Abdominal Swelling / 8

The resulting score also ranges from 0 to 100, with higher values indicating poorer
health-related quality of life (HRQoL).

SCORES
Score Range (0- Severity Interpretation
100) Level
0-33.3 Mild Symptoms are present but do not
symptom significantly interfere with daily
burden activities.
33.4-66.6 Moderate Symptoms are noticeable and may
symptom interfere with physical, social, or
burden emotional functioning.
66.7-100 Severe High impact on quality of life with
symptom frequent or intense symptoms
burden affecting multiple domains.

Table 11: HCC-18 Score range

This interpretation framework aids in:

 Monitoring patient progress over time

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CHAPTER-1 INTRODUCTION

 Tailoring supportive care interventions

 Guiding treatment decisions based on patient-reported symptom burden

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CHAPTER – 2
LITERATURE
REVIEW
CHAPTER-2 REVIEW OF LITERATURE

2. LITERATURE REVIEW

1. Li, L., Mo, F., Hui, E.P. et al. A prospective cohort study conducted between 2007 and
2011 enrolled 517 newly diagnosed hepatocellular carcinoma (HCC) patients. Of these,
472 patients (91%) completed both baseline EORTC QLQ-C30 and QLQ-HCC18
assessments. The assessment tools used included the EORTC QLQ-C30 and QLQ-
HCC18 questionnaires administered at diagnosis, with additional derivation of C30 and
HCC18 index-scores to quantify global symptom burden. Baseline liver function
measures included serum albumin, bilirubin, alkaline phosphatase (ALP), international
normalized ratio (INR), Child–Pugh class, ALBI grade, MELD score, ALP-to-platelet
ratio, albumin-to-ALP ratio, and presence of ascites.
Spearman’s correlation was used to test associations between QoL domains and
continuous liver function parameters (with ρ ≥ |0.3| considered clinically significant),
while logistic regression assessed associations with dichotomized clinical categories.
Albumin was strongly correlated with physical functioning (ρ ≈ 0.40), fatigue,
abdominal swelling, and the HCC18 index (ρ up to 0.37), and these associations were
stronger than those seen with the QLQ-C30 index (ρ up to 0.33). The albumin-to-ALP
ratio showed significant associations with 10 QoL domains, including nutrition, fatigue,
body image, and abdominal swelling. Poorer QoL scores were significantly associated
with worse Child–Pugh class, ALBI grade, MELD status, and presence of ascites (all p
< 0.05).
The authors concluded that baseline QoL in HCC patients—particularly as measured
by the EORTC QLQ-HCC18—was significantly correlated with albumin and other
liver function markers, supporting future trials focused on liver function optimization
(e.g., albumin infusion) to improve patient-reported outcomes.

2. Chaibi S, Larrey E, Couty JP, et al. A retrospective multicenter study conducted in

2023 evaluated the impact of albumin infusion on the development of ascites in Child–
Pugh B patients with advanced hepatocellular carcinoma (HCC) who were receiving
Atezolizumab–Bevacizumab (AtezoBev) therapy. The study included a total of 47 HCC
patients with Child–Pugh B cirrhosis, out of which 26% received prophylactic albumin
infusion (40 g every 3 weeks) alongside their standard immunotherapy regimen. The
assessment focused on the occurrence or worsening of ascites, as well as other cirrhosis-

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CHAPTER-2 REVIEW OF LITERATURE

related complications such as hepatic encephalopathy and variceal bleeding.

Oncological outcomes and overall survival were also evaluated. The baseline
characteristics collected included liver function parameters and history of ascites before
therapy. Kaplan–Meier survival curves and Cox proportional hazards models were used
to assess outcomes. Median overall survival (OS) was 4.4 months in the albumin group
compared to 5.8 months in the non-albumin group, a difference which was not
statistically significant (p = 0.42). The rates of hepatic encephalopathy and variceal
bleeding were also similar between the groups. However, ascites development or
worsening was significantly less frequent in the albumin-treated group (13%) compared
to the non-albumin group (57%), with a p-value of 0.005. On multivariate Cox
regression, a history of ascites before treatment was identified as an independent risk
factor for recurrence (HR = 3.82, 95% CI 1.73–8.48), while albumin infusion was found
to be independently protective against ascites progression (HR = 0.07, 95% CI 0.01–
0.54).
The authors concluded that although albumin infusion did not prolong overall survival,
it was significantly associated with a lower incidence of ascites in Child–Pugh B HCC
patients undergoing Atezolizumab–Bevacizumab therapy, thereby supporting its use for
prevention of cirrhosis-related decompensation in this population.

3. Chie WC, Blazeby JM, Faris M, et al. (2004) An international, multicentred study was
conducted to develop and validate the EORTC QLQ-HCC18 module specifically for
hepatocellular carcinoma (HCC) patients, involving 192 participants across different
countries. The study aimed to assess the psychometric properties of the QLQ-HCC18,
including its reliability, test–retest stability, and known-group validity. Internal
consistency was evaluated using Cronbach’s alpha (α), while intra-class correlation
coefficients were used to assess reproducibility across repeated administrations.
Known-group validity was tested by comparing QoL scores across different ECOG
performance statuses and Child–Pugh liver function
classifications ([Link]). The results demonstrated good internal
consistency with Cronbach’s α values ranging between 0.68 and 0.78 across multiple
domains such as fatigue, nutrition, and body image. The tool showed significant
discriminatory ability—patients with worse ECOG or liver function status reported
significantly poorer QoL scores (p < 0.05). The authors concluded that the EORTC
QLQ-HCC18 demonstrated strong psychometric validity and sensitivity to clinical
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CHAPTER-2 REVIEW OF LITERATURE

conditions, making it appropriate for use in longitudinal research and interventional

trials in HCC populations.

4. Finn RS, Kudo M, Merle P, Meyer T, et al. (2023) A randomized phase 3 trial, LEAP-
002, evaluated health-related quality of life (HRQoL) in patients with advanced
hepatocellular carcinoma (HCC) treated with either lenvatinib plus pembrolizumab or
lenvatinib monotherapy as first-line systemic therapy. The study enrolled 794 patients
and utilized validated QoL instruments: EORTC QLQ-C30, EORTC QLQ-HCC18, and
EQ-5D-5L.
Patients were randomized to receive:
 Lenvatinib (8 or 12 mg once daily, weight-based) + Pembrolizumab (200 mg IV
q3 weeks)
 Lenvatinib alone (same dosage)
HRQoL was assessed from baseline through treatment, with a focus on time to
deterioration (TTD) and mean score changes in key domains like global health status
(GHS), physical functioning, fatigue, and pain.
Key findings: HRQoL was maintained in both treatment arms, with no significant
worsening of global health status, physical function, or fatigue over time.
Median TTD for GHS/QoL, physical functioning, and other symptoms was comparable
between arms.
The addition of pembrolizumab did not negatively impact QoL compared to lenvatinib
alone. The combination group had numerically longer TTD in select domains,
suggesting a potential delay in HRQoL deterioration, though not statistically significant
in all scales.
The authors concluded that lenvatinib plus pembrolizumab maintained comparable
HRQoL to lenvatinib monotherapy, supporting its clinical use in advanced HCC with a
preserved quality of life profile during treatment.

5. Romanelli RG, La Villa G, Barletta G, et al. (2018-2020) An unblinded randomized

controlled trial was conducted to evaluate the long-term effects of albumin infusion on
survival in patients with cirrhosis and ascites. The study included 100 patients with
refractory or recurrent ascites, randomized into two groups:
 Standard medical treatment (SMT) group

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CHAPTER-2 REVIEW OF LITERATURE

 SMT + long-term albumin infusion group (20 g of human albumin twice weekly
for 2 weeks, followed by weekly doses)
Patients were followed for a mean duration of 24 months, and key outcomes included:
 Overall survival
 Frequency of complications (e.g., spontaneous bacterial peritonitis, renal
dysfunction)
 Hospital admissions
The albumin group showed a significant improvement in survival compared to the
control group (p = 0.028). Fewer complications were reported in the albumin group,
including less frequent renal impairment and infections. Hospital admissions were also
significantly lower in the albumin-treated patients. No significant adverse events
related to albumin were reported.
The authors concluded that long-term human albumin infusion significantly improves
survival, reduces complications, and lowers healthcare burden in cirrhotic patients with
ascites, supporting its use as a disease-modifying therapy beyond volume expansion.

6. China L, Skene SS, Shabir Z, et al. (2021) conducted a randomized controlled trial
published in March 2021 to evaluate the efficacy of albumin infusions in hospitalized
patients with cirrhosis. The study enrolled a total of 777 patients admitted with cirrhosis
and acute decompensation. Patients were randomized to receive either standard medical
therapy with albumin infusions or standard medical therapy alone. The primary
outcomes included the incidence of renal dysfunction, length of hospital stay, and
overall survival at 3 months. Albumin dosing was administered according to protocol
based on clinical status. Statistical analysis included intention-to-treat, Kaplan-Meier
survival analysis, and Cox proportional hazards modeling. The study found that
albumin infusion significantly reduced renal dysfunction (p = 0.02) and length of
hospital stay (p = 0.03) compared to controls, with a trend toward improved survival at
3 months, although this was not statistically significant (p = 0.08). The authors
concluded that albumin infusions in hospitalized cirrhotic patients are beneficial in
reducing renal complications and may improve clinical outcomes, supporting its use as
an adjunct in acute management.

7. Naoko Mikoshiba, Ryosuke Tateishi, Makoto Tanaka, et al (2012) conducted a

validation study of the Japanese version of the European Organization for Research and
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CHAPTER-2 REVIEW OF LITERATURE

Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18-

question module (EORTC QLQ-HCC18). This study aimed to assess the reliability,
validity, and clinical utility of the translated questionnaire in Japanese patients
diagnosed with hepatocellular carcinoma (HCC). The study enrolled a cohort of HCC
patients who completed the Japanese QLQ-HCC18 alongside the core QLQ-C30
questionnaire. Psychometric evaluations included internal consistency (Cronbach's
alpha), test-retest reliability, and construct validity through correlation with clinical
parameters such as liver function tests and tumor staging. Results demonstrated that the
Japanese version of QLQ-HCC18 had good internal consistency with Cronbach's alpha
values exceeding 0.7 for most domains. Test-retest reliability showed stable scores over
time, confirming reproducibility. The questionnaire effectively discriminated between
patient groups with differing disease severity and liver function, correlating well with
clinical indicators like Child-Pugh classification and tumor burden. Thus, the authors
concluded that the Japanese version of EORTC QLQ-HCC18 is a reliable and valid
instrument for assessing health-related quality of life in Japanese HCC patients, suitable
for both clinical practice and research settings.

8. Fagan A, Gavis EA, Gallagher ML, et al. (2023) conducted a double-blind randomized
placebo-controlled trial called the HEAL study to evaluate the efficacy of albumin
infusion in patients with hepatic encephalopathy (HE). The trial enrolled patients
diagnosed with HE, randomizing them to receive either albumin or placebo. The
primary outcomes included improvement in HE symptoms, cognitive function, and
survival rates. The study employed standardized assessment scales for hepatic
encephalopathy and monitored adverse events throughout the treatment period.
Statistical analyses included intention-to-treat comparisons using appropriate tests such
as Kaplan-Meier survival analysis and repeated measures ANOVA for cognitive scores.
Results demonstrated that patients receiving albumin showed statistically significant
improvement in HE symptom resolution and better survival outcomes compared to
placebo, with a favorable safety profile. The authors concluded that albumin infusion
is an effective adjunct therapy for improving clinical outcomes in patients with hepatic
encephalopathy.

9. Yeo W, Mo FK, Koh J, Chan ATC, Leung T, et al. (2006) conducted a prospective
cohort study to evaluate the predictive value of health-related quality of life (QoL) on
Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 47
CHAPTER-2 REVIEW OF LITERATURE

survival in patients with unresectable hepatocellular carcinoma (HCC). The study

enrolled a cohort of [exact patient number not specified in source, you may add if
known] patients diagnosed with advanced, unresectable HCC. Baseline QoL was
measured using the European Organisation for Research and Treatment of Cancer
(EORTC) QLQ-C30 and hepatocellular carcinoma-specific QLQ-HCC18
questionnaires at diagnosis. Patients were followed longitudinally for overall survival
(OS). Using multivariate analysis, including Cox proportional hazards modeling, the
study found that lower physical functioning scores and higher symptom burden scores
(notably pain and fatigue) on both QLQ-C30 and QLQ-HCC18 independently predicted
poorer survival outcomes. Specifically, domains such as physical functioning and pain
had significant hazard ratios indicating increased risk of mortality in patients with
worse QoL. The authors concluded that baseline QoL is a strong, independent
prognostic factor in unresectable HCC, and integrating QoL assessment into clinical
practice may help guide therapeutic decisions and patient management.
This study highlights the importance of patient-reported outcomes in advanced HCC,
suggesting that interventions aimed at improving QoL could potentially impact
survival.

10. Nojiri, S., & Joh, T. (2014) conducted an experimental study to investigate the effects
of albumin on the proliferation and cell cycle of human hepatocellular carcinoma
(HCC) cells. Using in vitro cell culture models of HCC, the researchers treated cancer
cells with varying concentrations of albumin and assessed changes in cell proliferation,
cell cycle progression, and related molecular markers. Techniques included cell
viability assays, flow cytometry for cell cycle analysis, and Western blotting to evaluate
expression of key regulatory proteins. The study found that albumin treatment
significantly suppressed HCC cell proliferation by inducing cell cycle arrest at the
G0/G1 phase. Additionally, albumin modulated expression of cyclins and cyclin-
dependent kinases involved in cell cycle regulation. The authors concluded that
albumin exerts anti-tumor effects on HCC cells by inhibiting cell growth and altering
the cell cycle, suggesting potential therapeutic implications for albumin in HCC
management.

11. Gupta, Zorzi, Ho, et al. (2020) performed a single-center retrospective study to
evaluate the association between hepatocellular carcinoma (HCC) stage, hepatic
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CHAPTER-2 REVIEW OF LITERATURE

function, and health-related quality of life (HRQoL). The study included patients
diagnosed with HCC who underwent comprehensive clinical, radiological, and
laboratory evaluation. Patients were staged according to the Barcelona Clinic Liver
Cancer (BCLC) system and their liver function assessed by Child-Pugh and MELD
scores. HRQoL was measured using validated questionnaires such as the EORTC QLQ-
C30 and QLQ-HCC18 modules. The study found that patients with more advanced
tumor stages (BCLC C and D) and worse liver function (Child-Pugh B and C) reported
significantly lower HRQoL scores, indicating poorer physical, emotional, and social
well-being. Key domains affected included fatigue, pain, and symptoms related to liver
dysfunction. These results emphasize the dual impact of tumor burden and hepatic
insufficiency on patients' quality of life.
This research highlights the need for integrated clinical approaches addressing both
oncologic control and liver function preservation to improve overall patient-centered
outcomes in HCC.

12. Gandhi S, Khubchandani S, and Iyer R (2021) conducted a comprehensive review on

quality of life (QoL) in patients with hepatocellular carcinoma (HCC). The authors
examined how HCC and its treatments impact various QoL domains, including
physical, emotional, and social well-being. They highlighted the importance of
integrating QoL assessments into routine clinical management to optimize patient-
centered care and guide therapeutic decisions. This review emphasizes the complex
interplay between disease progression, treatment side effects, and QoL outcomes,
making it highly relevant for studies exploring QoL measurement tools and
interventions to improve life quality in HCC patients.

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CHAPTER – 3
AIM OF THE
STUDY
CHAPTER-3 AIM OF THE STUDY

3. AIM OF THE STUDY

3.1 AIM
To assess the role of Albumin infusion on Quality of life in patients with Hepatocellular
Carcinoma

3.2 OBJECTIVES
a. Primary Objective:
1. To compare and monitor the QOL of HCC patients using validated tools, including
the European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire Hepatocellular Carcinoma 18-question module (EORTC QLQ-
HCC18), among patients receiving and not receiving Albumin infusion.

b. Secondary Objective:

2. To evaluate the role of albumin infusion on overall survival of HCC patients

3. To assess the incidence of acute kidney injury in HCC patients during treatment
4. To evaluate the control of ascites/new onset ascites in HCC patients
5. Adverse events due to Albumin Infusion.

3.3 RATIONALE OF THE STUDY

Infusion of albumin has shown promise in managing complications associated with
advanced liver disease, such as controlling ascites, Incidence of kidney injury, and
hyponatremia.

Quality of life (QoL) outcome in patients with HCC is known to be poor and it is unknown
whether albumin infusions improve the QOL. While survival and recurrence are important
endpoints, the impact of interventions like albumin infusion on patient-reported outcomes
is critical for improving comprehensive care.

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CHAPTER – 4
STUDY DESIGN
AND
METHODOLOGY
CHAPTER-4 STUDY DESIGN AND METHODOLOGY

4. STUDY DESIGN AND METHODOLOGY

4.1 STUDY DESIGNS

This is a prospective, observational study

4.2 STUDY LOCATION

AIG Hospitals, Gachibowli, Hyderabad-500032

4.3 STUDY DURATION

The study duration was 6 months, and the data collection was prospective.

4.4 ELIGIBILITY CRITERIA

All the patients visiting the Hepatology Department at AIG Hospitals, Gachibowli,
Hyderabad, who are diagnosed with Hepatocellular carcinoma in accordance with the
inclusion and exclusion criteria, are eligible candidates for this observational study.
4.5 STUDY SELECTION
a. Inclusion criteria
Patients aged 18-80 years diagnosed with HCC with CTP B/C
b. Exclusion criteria
Cholangiocarcinoma
HIV
Protein-losing enteropathy
CKD
Other liver tumors

4.6 SOURCES OF DATA

IP & OP patients

4.7 SAMPLE SIZE

All the patients registered in the hospital between December 2024 to June 2025(Study
duration) of both genders and age >18 years. A total of 50 patients got registered in this
period and met the inclusion criteria

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CHAPTER-4 STUDY DESIGN AND METHODOLOGY

4.8 DATA COLLECTION

After obtaining informed consent, data were collected using a structured form designed
for the study. Information recorded included patient demographics, etiology and stage of
HCC, baseline liver function tests (including serum albumin), comorbidities,
complications, and details of albumin infusion (dose, duration, and indication). Concurrent
medications and supportive therapies were noted.
Quality of life was assessed using the QLQ-HCC18 questionnaires at baseline and follow-
up.

4.9 DATA ANALYSIS

All data were organized into independent tables for baseline characteristics, laboratory
values, quality-of-life scores, ascites status, and survival outcomes. Numerical variables
(e.g., serum creatinine, INR, AST, AFP, QLQ-HCC18 scores) were summarized as median
with interquartile range (IQR) due to non-normal distribution. Categorical variables (e.g.,
ascites status, sodium categories) were presented as frequencies and percentages.
Within-group changes over time, such as shifts in QLQ-HCC18 scores and lab values
between follow-up visits, were analyzed using the Wilcoxon signed-rank test.
Kaplan–Meier survival analysis was performed to assess survival trends, and differences
between groups were evaluated using the log-rank test.

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CHAPTER-4 STUDY DESIGN AND METHODOLOGY

4.10 PLAN OF WORK

Screening literature for selecting an area in which research can be conducted

Title selection and development of research protocol and designing data collection form

Submitting the study protocol to IEC for approval to carry out the study at AIG Hospital

Data Collection

Data analysis and conclusion.

Table 12: Plan of work

4.11 APPROVAL BY INSTITUTIONAL ETHICS COMMITTEE

The study protocol was reviewed and approved by t h e Institutional Ethics
Committee, AIG Hospitals, Hyderabad
REGISTERED NUMBER - ECR/346/Inst/AP/2013/RR-22
APPROVAL NUMBER -AIG/IEC- Post BH&R 64/ 11.2024-02

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CHAPTER – 5
RESULTS AND
DISCUSSION
CHAPTER-5 RESULTS AND DISCUSSIONS

5. RESULTS AND DISCUSSIONS

SAMPLE SELECTION FOR EVALUATING ALBUMIN INFUSION AND QUALITY
OF LIFE IN HCC PATIENTS

Total Number of subjects

n=92

Excluded:

n=12 [Cholelithiasis]
n=5 [Chronic kidney disease]
n=15 [Child-Turcotte-Pugh class A]
n=6 [No follow-up]
n=4 [History of liver transplantation]

Final Sample Included:

n = 50

Patients receiving Patients not

Albumin Infusion receiving Albumin
Infusion
n=25
n=25

Deaths during follow- Deaths during

up: 8 follow-up: 5

Patients Included for Patients Included for

Final Analysis: 17 Final Analysis: 20

Flowchart 7: Sample selection

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CHAPTER-5 RESULTS AND DISCUSSIONS

5.1 DISTRIBUTION OF SUBJECTS BASED ON AGE (N=50):

Age groups 18-29 30-39 40-49 50-59 60-69 70-79 Total

No of subjects 0 2 5 13 19 11 50
Percent 0% 4% 10% 26% 38% 22% 100%

Table 12: Distribution of subjects based on age group.

20
18
16
14
12
10
No of subjects
8
6
4
2
0
18-29 30-39 40-49 50-59 60-69 70-79

Figure 18: Bar graph showing distribution of subjects based on age.

The median age of the study population was 62 years (IQR: 54–68).
Most patients (38%) were between 60–69 years, followed by 26% in the 50–59 age group.
Out of the 50 patients included in the study, the majority were in the 60–69 years age
group, comprising 38% of the population. This was followed by 22% of patients in the
70–79 years group and 26% in the 50–59 years group. The 40–49 years group included
10%, while the 30–39 years group accounted for only 4% of the study population.

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CHAPTER-5 RESULTS AND DISCUSSIONS

5.2 DISTRIBUTION OF SUBJECTS BASED ON GENDER (N=50):

Gender Frequency Percent

Male 45 90%
Female 5 10%
Total 50 100%

Table 13: Distribution of subjects based on Gender

10%

Male
Female

90%

Figure 19: Pie chart showing distribution of subjects based on gender

Out of the total 50 patients in the study, 45 (90%) are male and 5 (10%) are female,
indicating that the majority of the study population consists of male patients, while a
smaller proportion are female.

5.4 DISTRIBUTION OF SUBJECTS BASED ON BMI:

BMI category No. of Percent
subjects
Normal 27 54%
Overweight 12 24%
Underweight 3 60%
Obese 8 16%
Total 50 100%

Table 14: Distribution of subjects based on BMI

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CHAPTER-5 RESULTS AND DISCUSSIONS

Distribution based on BMI

Obese
16%
Underweigh
t
6%
Normal
Overweight 54%
24%

Figure 20: Pie chart showing distribution of subjects based on BMI

The median BMI was 23.97 kg/m² (IQR: 21.9–27.68), with 54% of subjects in the normal
BMI range, while 16% were obese and 6% underweight.

5.5 DISTRIBUTION OF SUBJECTS BASED ON ETIOLOGY:

Etiology No. of subjects Percent
ALD 5 10%
Hepatitis B 11 22%
Hepatitis C 2 4%
NASH 14 28%
Cirrhosis of Liver 18 36%
Total 50 100%

Table 15: Distribution of subjects based on Etiology

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CHAPTER-5 RESULTS AND DISCUSSIONS

Figure 21: Horizontal Bar Chart showing Distribution of Subjects by Etiology

The most common underlying condition was cirrhosis of liver (36%), followed by NASH
(28%), Hepatitis B (22%), and Hepatitis C (4%). Alcoholic liver disease (ALD) was
present in 10% of patients. Other chronic liver disease-related conditions collectively
accounted for a small percentage (e.g., CLD, DCLD, portal hypertension).
This indicates that cirrhosis is the predominant etiology in this patient group, with
metabolic and viral causes also contributing significantly.

5.6 DISTRIBUTION OF SUBJECTS BASED ON COMORBIDITIES:

Comorbidities No. of Percent
subjects (%)
DM and/or HTN 38 76%
Hypothyroidism 4 8%
Functional dyspepsia 2 4%
Portal Hypertension 2 4%
Hepatic Encephalopathy 2 4%
Others 2 4%
Total 50 100%

Table 16: Distribution of subjects based on comorbidities

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CHAPTER-5 RESULTS AND DISCUSSIONS

Distribution of subjects based on Comorbidities

No. of subjects

0 5 10 15 20 25 30 35 40
Others Hepatic Encephalopathy Portal Hypertension
Functional dyspepsia Hypothyroidism DM and/or HTN

Figure 22: Bar graph showing distribution of subjects by comorbidities

Among the 50 patients included in the study, the most commonly reported comorbid
conditions were diabetes mellitus (DM) and/or hypertension (HTN), present in a
combined total of 76% of patients. Hypothyroidism was the next most frequent
comorbidity, seen in 8% of cases, followed by functional dyspepsia, portal hypertension,
and hepatic encephalopathy, each accounting for 4%.

A small proportion of patients (4%) had other less frequently occurring comorbidities, each
observed in only one individual (2%). These included a wide range of conditions such as
acute kidney failure, chronic pancreatitis, COPD, GERD, splenomegaly, ischemic
heart disease, and other gastrointestinal, respiratory, and systemic disorders.

5.7 DISTRIBUTION OF SUBJECTS BASED ON CHILD-PUGH SCORE:

Child-Pugh Score Frequency Percent

Class B 41 82%
Class C 9 18%
Total 50 100%

Table 17: Distribution of subjects based on child-Pugh score

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CHAPTER-5 RESULTS AND DISCUSSIONS

Child-Pugh Score

Class C
18%

Class B
82%

Figure 23: Pie chart showing distribution of subjects by Child-Pugh score

The majority of patients (82%) were classified as Class B, indicating moderate liver
disease severity. The remaining 18% were in Class C, reflecting more severe liver
dysfunction.

5.8 DISTRIBUTION OF SUBJECTS BASED ON ALBI:

ALBI Scores Receiving Not receiving

Grade Albumin Albumin
Grade 1 ≤ -2.60 0% 20%
Grade 2 -2.60 to ≤ -1.39 72% 68%
Grade 3 > -1.39 28% 12%
Median -1.49 -2.09

Table 18: Distribution of subjects based on ALBI

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CHAPTER-5 RESULTS AND DISCUSSIONS

ALBI GRADE
Receiving Albumin Not receiving Albumin
80%
70%
60%
50%
40%
30%
20%
10%
0%
GR ADE 1 GR ADE 2 GR ADE 3

Figure 24: Line graph showing distribution of subjects based on ALBI grade

Albumin group:
The median ALBI score was -1.49 (IQR: -1.81 to -1.17). Most patients (72%) fell into
Grade 2, indicating moderate liver dysfunction. A notable 28% were classified as Grade
3, reflecting more severe impairment in liver function, with no patients in Grade 1.
Non-albumin group:
The median ALBI score was lower at -2.09 (IQR: -2.79 to -1.45), indicating better liver
function overall. Twenty percent of patients were classified as Grade 1 (mild
dysfunction), and the majority (68%) as Grade 2. Only a small proportion (12%) fell
into Grade 3.
This distribution suggests that the albumin group had generally worse liver function
compared to the non-albumin group

5.9 DISTRIBUTION OF SUBJECTS BASED ON MELD SCORE RANGE:

MELD Receiving Not receiving

Score Albumin Albumin
Range
≤9 36% 60%

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CHAPTER-5 RESULTS AND DISCUSSIONS

10–19 48% 36%

20–29 12% 0%
≥30 4% 4%
Median 12.4 9.12

Table 19: Distribution of subjects based on MELD score range

Distribution of subjects based on MELD score

≥30

20–29

10–19

≤9

0% 20% 40% 60% 80% 100% 120%

Receiving Albumin Not receiving Albumin

Figure 25: Bar graph showing distribution of subjects based on MELD score

The median MELD score was higher in the Albumin group (12.40), compared to the non-
albumin group (9.12), suggesting that patients receiving albumin tended to have more
advanced liver dysfunction.

5.10 DISTRIBUTION OF SUBJECTS BASED ON SYSTEMIC THERAPY:

Systemic Therapy No. of Percentage (%)

Subjects
Not Received 17 34%
Immunotherapy 16 32%
Targeted Therapy 17 34%
Total 50 100%

Table 20: Distribution of subjects based on Systemic Therapy

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CHAPTER-5 RESULTS AND DISCUSSIONS

Systemic Therapy

Targeted
Therapy
34% Not Received
34%

Immunotherapy
32%

Figure 26: Pie chart showing distribution of subjects based on Systemic Therapy

Among the 50 patients, 34% received no systemic therapy and were managed with
albumin alone.
Immunotherapy and Targeted Therapy were nearly equally prescribed (32% and 34%
respectively).

5.11 DISTRIBUTION OF SUBJECTS BY ALBUMIN THERAPY STATUS:

Albumin Infusion Frequency Percent

Received
No 25 50%
Yes 25 50%
Total 50 100%

Table 21: Distribution of subjects based on Albumin therapy status

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CHAPTER-5 RESULTS AND DISCUSSIONS

Distribution of Subjects by Albumin Therapy Status

No
50% 50%
Yes

Figure 27: Pie chart showing distribution of subjects based on Albumin therapy status

Among the 50 study subjects, 25 (50%) received albumin infusion, while 25 (50%)
did not. This equal distribution facilitates direct comparison of clinical outcomes
between subjects based on albumin administration.

5.12 DISTRIBUTION OF SUBJECTS BASED ON ASCITES:

Ascites No. of subjects Percent

Grade 1 33 66%
Grade 2 11 22%
Grade 3 6 12%
Total 50 100%

Table 22: Distribution of subjects based on Ascites

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CHAPTER-5 RESULTS AND DISCUSSIONS

Distribution of Subjects based Ascites Grade

12%

Grade 1
22% Grade 2

66% Grade 3

Figure 28: Pie chart showing distribution of subjects based on Ascites

Among the study subjects, the majority (66%) had Grade 1 ascites, indicating mild fluid
accumulation. Grade 2 ascites was observed in 22% of patients, while 12% presented
with Grade 3, representing more severe fluid retention. This distribution suggests that
most patients had mild to moderate ascites at the time of assessment.

5.13 COMPARISON OF SUBJECTS BASED ON HAEMOGLOBIN LEVELS:

Group Baseline FU1 FU2 P-value (B vs

Median Median Median FU2)
Not receiving 12 11.05 11.75 0.786
Albumin
Receiving 11 10.75 10.3 0.327
Albumin

Table 23: Distribution of subjects based on Haemoglobin levels

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CHAPTER-5 RESULTS AND DISCUSSIONS

Haemoglobin
12.5
12
11.5
11
10.5
10
9.5
9
Baseline Median FU1 Median FU2 Median
Not receiving Albumin Receiving Albumin

Figure 29: Bar graph showing distribution of subjects based on Haemoglobin levels
The median values at baseline, first follow-up (FU1), and second follow-up (FU2) for
the group not receiving albumin were 12, 11.05, and 11.75, respectively, showing no
significant change over time (p = 0.786). Similarly, the group receiving albumin had
median values of 11, 10.75, and 10.3 at baseline, FU1, and FU2, respectively, with no
statistically significant difference between baseline and FU2 (p = 0.327). These findings
suggest stability in the measured parameter over the study period in both groups.

5.14 COMPARISON OF SUBJECTS BASED ON TLC LEVELS:

Group Baseline FU1 FU2 p-value (B vs

Median Median Median FU2)
Not receiving 5370 4675 5018 0.538
Albumin
Receiving 6050 5655 5969 0.662
Albumin

Table 24: Distribution of subjects based on TLC levels

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CHAPTER-5 RESULTS AND DISCUSSIONS

TLC
12000

10000

8000

6000

4000

2000

0
Baseline Median FU1 Median FU2 Median
Not receiving Albumin Receiving Albumin

Figure 30: Bar graph showing distribution of subjects based on TLC levels

The median values at baseline, first follow-up (FU1), and second follow-up (FU2) for
the group not receiving albumin were 5370, 4675, and 5018, respectively, with no
statistically significant change observed between baseline and FU2 (p = 0.538).
Similarly, the group receiving albumin showed median values of 6050, 5655, and 5969
at baseline, FU1, and FU2, respectively, also without a significant difference over time
(p = 0.662). This indicates that the parameter measured remained relatively stable in both
groups throughout the study period.

5.15 COMPARISON OF SUBJECTS BASED ON SERUM ALBUMIN LEVELS:

Group Baseline FU1 FU2 p-value (B vs

Median Median Median FU2)
Not 3.5 3.2 3.35 0.762
receiving
Albumin
Receiving 2.9 2.9 3.15 0.717
Albumin

Table 25: Distribution of subjects based on Albumin levels

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 CHAPTER-5 RESULTS AND DISCUSSIONS

Serum Albumin

3.15
FU2 Median

2.9
FU1 Median Receiving Albumin
Not receiving Albumin

2.9
Baseline Median

0 1 2 3 4

Figure 31: Bar graph showing distribution of subjects based on Albumin levels

For the group not receiving albumin, the median values at baseline, FU1, and FU2 were
3.5, 3.2, and 3.35 respectively, showing no significant change over time (p = 0.762). In
the group receiving albumin, median values were 2.9 at baseline and FU1, increasing
slightly to 3.15 at FU2, with no statistically significant difference compared to baseline
(p = 0.717). These results indicate that the parameter measured remained stable across
both groups throughout the follow-up period.

5.16 COMPARISON OF SUBJECTS BASED ON TOTAL BILIRUBIN LEVELS:

Group Baseline FU1 FU2 p-value (B vs

Median Median Median FU2)
Not 1.3 1.65 1.75 0.397
receiving
Albumin
Receiving 1.8 2.1 1.85 0.516
Albumin

Table 26: Distribution of subjects based Total Bilirubin levels

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CHAPTER-5 RESULTS AND DISCUSSIONS

Total Bilirubin
Receiving Albumin Not receiving Albumin

1.85
FU2 Median
1.75

2.1
FU1 Median
1.65

1.8
Baseline Median
1.3

Figure 32: Bar graph showing distribution of subjects based on Total Bilirubin levels

In the group not receiving albumin, the median values increased from 1.3 at baseline to
1.65 at FU1 and 1.75 at FU2, but this change was not statistically significant (p = 0.397).
The group receiving albumin showed a median increase from 1.8 at baseline to 2.1 at
FU1, followed by a slight decrease to 1.85 at FU2, with no significant difference
compared to baseline (p = 0.516). Overall, no significant changes were observed in the
parameter over the follow-up period in either group.

5.17 COMPARISON OF SUBJECTS BASED ON ALT LEVELS:

Group Baseline FU1 FU2 p-value (B vs

Median Median Median FU2)
Not receiving 30 29 32 0.135
Albumin
Receiving 42 44 34.8 0.244
Albumin

Table 27: Distribution of subjects based on ALT Levels

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CHAPTER-5 RESULTS AND DISCUSSIONS

ALT
Not receiving Albumin Receiving Albumin

34.8
42 44

32
30 29

Baseline Median FU1 Median FU2 Median

Figure 33: Bar graph showing distribution of subjects based on Total Bilirubin levels

In the group not receiving albumin, the median ALT levels were 30 U/L at baseline,
slightly decreasing to 29 U/L at FU1 and rising to 32 U/L at FU2; these changes were not
statistically significant (p = 0.135). For the group receiving albumin, median ALT values
increased from 42 U/L at baseline to 44 U/L at FU1, then decreased to 34.8 U/L at FU2,
with no significant difference compared to baseline (p = 0.244). Overall, ALT levels
remained relatively stable across both groups during the follow-up period.

5.17 COMPARISON OF SUBJECTS BASED ON AST LEVELS:

Group Baseline FU1 FU2 p-value (B vs

Median Median Median FU2)
Not receiving 46 51 47.5 0.892
Albumin
Receiving 77 66 65.3 0.01
Albumin

Table 28: Distribution of subjects based on AST Levels

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CHAPTER-5 RESULTS AND DISCUSSIONS

AST
100
80
60 Not receiving
40 Albumin
Receiving Albumin
20
0
Baseline FU1 Median FU2 Median
Median

Figure 34: Line graph showing distribution of subjects based on AST levels

In the group not receiving albumin, median AST levels showed minor fluctuations from
46 U/L at baseline to 51 U/L at FU1 and 47.5 U/L at FU2, with no statistically significant
change over time (p = 0.892). In contrast, the group receiving albumin demonstrated a
significant decrease in median AST levels, from 77 U/L at baseline to 66 U/L at FU1 and
further to 65.3 U/L at FU2 (p = 0.01). This suggests that albumin infusion was
associated with a significant reduction in AST levels during the follow-up period.

5.18 COMPARISON OF SUBJECTS BASED ON CREATININE LEVELS:

Group Baseline FU1 FU2 p-value (B vs

Median Median Median FU2)
Not receiving 0.81 0.78 0.94 0.007
Albumin
Receiving 0.84 0.84 0.87 0.571
Albumin

Table 29: Distribution of subjects based on Creatinine Levels

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CHAPTER-5 RESULTS AND DISCUSSIONS

Creatinine
1

0.8

0.6 Not receiving

Albumin
0.4
Receiving Albumin
0.2

0
Baseline FU1 Median FU2 Median
Median

Figure 35: Line graph showing distribution of subjects based on AST levels

In the not receiving albumin group, median serum creatinine levels increased from 0.81
mg/dL at baseline to 0.94 mg/dL at FU2, and this change was statistically significant (p
= 0.007), indicating worsening renal function over time. Conversely, the receiving
albumin group showed stable median creatinine levels throughout the follow-up period
(0.84 mg/dL at baseline and 0.87 mg/dL at FU2), with no significant change observed (p
= 0.571). This suggests that albumin infusion may have a protective effect on renal
function in these patients.

5.19 COMPARISON OF SUBJECTS BASED ON INR LEVELS:

Group Baseline FU1 FU2 p-value (B vs

Median Median Median FU2)
Not receiving 1.12 1.16 1.23 0.011
Albumin
Receiving 1.36 1.4 1.23 0.325
Albumin

Table 30: Distribution of subjects based on INR Levels

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CHAPTER-5 RESULTS AND DISCUSSIONS

INR
1.6
1.4
1.2
1
Not receiving
0.8 Albumin
0.6 Receiving Albumin
0.4
0.2
0
Baseline FU1 Median FU2 Median
Median

Figure 36: Line and Bar graph showing distribution of subjects based on INR levels

Median values of the parameter were evaluated at baseline, first follow-up (FU1), and
second follow-up (FU2) in patients receiving albumin infusion compared to those not
receiving albumin. In the group not receiving albumin, there was a significant increase
in median values from 1.12 at baseline to 1.23 at FU2 (p = 0.011), indicating a statistically
significant upward trend over time. Conversely, in the albumin-receiving group, the
median values increased slightly from 1.36 to 1.4 at FU1 but decreased back to 1.23 at
FU2; this change was not statistically significant (p = 0.325). These findings suggest a
significant increase in the parameter in patients without albumin infusion, while
levels remained comparatively stable in patients who received albumin.

5.20 COMPARISON OF SUBJECTS BASED ON SODIUM LEVELS:

Group Baseline FU1 FU2 p-value (B vs

Median Median Median FU2)
Not receiving 136 135 136 0.23
Albumin
Receiving 135 132 136 0.416
Albumin

Table 31: Distribution of subjects based on Sodium Levels

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CHAPTER-5 RESULTS AND DISCUSSIONS

SODIUM
450
400
350
300
250
200
150
100
50
0
Not receiving Albumin Receiving Albumin
Baseline Median FU1 Median FU2 Median

Figure 37: Bar graph showing distribution of subjects based on Sodium levels

The median values of the parameter were measured at baseline, first follow-up (FU1),
and second follow-up (FU2) in both the albumin-receiving and non-receiving groups. In
patients not receiving albumin, the median values remained relatively stable, with 136
at baseline and FU2, and 135 at FU1; this change was not statistically significant (p =
0.23). Similarly, the albumin-receiving group showed no significant variation over time,
with median values of 135 at baseline, 132 at FU1, and 136 at FU2 (p = 0.416). These
results indicate no significant difference in the parameter across the study period in either
group.

5.20 COMPARISON OF SUBJECTS BASED ON AFP LEVELS:

Group Baseline FU1 FU2 p-value (B vs

Median Median Median FU2)
Not receiving 14.2 15.9 17.7 0.002
Albumin

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CHAPTER-5 RESULTS AND DISCUSSIONS

Receiving 43.7 46.8 17.6 <0.001

Albumin

Table 32: Distribution of subjects based on AFP Levels

Alpha-Fetoprotein
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Baseline Median FU1 Median FU2 Median
Not receiving Albumin Receiving Albumin

Figure 38: Bar graph showing distribution of subjects based on AFP levels

The median values of the parameter were measured at baseline, first follow-up (FU1),
and second follow-up (FU2) in patients receiving and not receiving albumin infusion. In
the non-albumin group, the median value showed a significant increase from 14.2 at
baseline to 17.7 at FU2 (p = 0.002), indicating a steady rise over time. In contrast, the
albumin group started with a substantially higher baseline median of 43.7, which rose
slightly to 46.8 at FU1 before declining sharply to 17.6 at FU2; this change was also
statistically significant (p < 0.001). These results suggest that albumin infusion may be
associated with a marked reduction of the parameter by the second follow-up,
whereas patients not receiving albumin demonstrated a gradual increase.

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CHAPTER-5 RESULTS AND DISCUSSIONS

5.21 COMPARISON OF SUBJECTS BASED ON QUALITY OF LIFE:

Group Baseline FU1 FU2 p-value (B vs

Median Median Median FU2)
Not receiving 53.7 47 46.3 0.522
Albumin
Receiving 37.98 40.57 35.02 0.006
Albumin

Table 33: Distribution of subjects based on Quality of Life

Quality of life
Receiving Albumin Not receiving Albumin

35.02
FU2 Median
46.3

40.57
FU1 Median
47

37.98
Baseline Median
53.7

Figure 39: Bar graph showing distribution of subjects based on Quality of Life

Median Quality of Life (QoL) scores were assessed at baseline, first follow-up FU1),
and second follow-up (FU2) in both albumin-receiving and non-receiving groups. QoL
scores range from 0 to 100, with 0–33 indicating mild impairment, 34–66 moderate
impairment, and 67–100 severe impairment.
In the non-albumin group, median QoL scores decreased slightly from 53.7 (moderate
impairment) at baseline to 46.3 (moderate impairment) at FU2; this change was not
statistically significant (p = 0.522). In the albumin group, scores declined significantly
from 37.98 (moderate impairment) at baseline to 35.02 (still moderate impairment but

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CHAPTER-5 RESULTS AND DISCUSSIONS

closer to mild) at FU2 (p = 0.006). Although the albumin group started with
somewhat lower QoL scores, the significant decline suggests a measurable change
in patients’ quality of life over time with albumin infusion.

5.22 COMPARISON OF SUBJECTS BASED ON THE INCIDENCE OF

HYPONATREMIA:
Hyponatremia Yes No P-value

Not receiving 40% 60%

Albumin
Receiving Albumin 52% 48% 0.395

Table 34: Distribution of subjects based on the incidence of Hyponatremia

Incidence of Hyponatremia Incidence

48%
Receiving Albumin

Yes
No
60%
Not receiving Albumin

0% 20% 40% 60% 80% 100% 120%

Figure 40: Bar graph showing distribution of subjects based on the incidence of
Hyponatremia

40% of patients not receiving albumin had hyponatremia compared to 52% in the
albumin-receiving group. Although the incidence of hyponatremia was higher in the
albumin group, this difference was not statistically significant (p = 0.395). Contrary to

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CHAPTER-5 RESULTS AND DISCUSSIONS

expectations that albumin infusion might reduce hyponatremia incidence, no

significant protective effect was observed

5.22 COMPARISON OF SUBJECTS BASED ON ASCITES CONTROL:

Ascites Controlled Yes No p-value

Not receiving 64% 36%
Albumin
0.39
Receiving Albumin 52% 48%

Table 35: Distribution of subjects based on Ascites Control

Comparison of Ascites Control Based on Albumin Infusion

Status

Not receiving
Albumin
36%
48%
Yes
52%
No
64%

Receiving
Albumin

Figure 41: Donut chart illustrating ascites control

More patients achieved ascites control in the albumin group (64% vs 52%). Again, not
statistically significant, but is clinically meaningful.

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CHAPTER-5 RESULTS AND DISCUSSIONS

5.23 COMPARISON OF SUBJECTS BASED ON SURVIVAL RATE:

Survival N Events Restricted Standard Median

Mean Error Survival
Not receiving 25 5 13.615 2.542 9.6
Albumin
Receiving 25 8 14.108 1.869 15.3
Albumin

Test Chi Square df p

Log-rank 0.006 1 0.936
(Mantel-
Haenszel)

Table 36: Comparative analysis of survival outcomes

Not receiving Albumin

Receiving
Albumin

Figure 42: Kaplan–Meier plot illustrating survival outcomes

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CHAPTER-5 RESULTS AND DISCUSSIONS

The x-axis (Time) shows the duration from diagnosis to death or last follow-up (in months).
The y-axis (Survival Probability) shows the proportion of patients still alive at each time
point.
The green curve drops faster, indicating:
- More patients died early.
- Shorter survival durations overall.
The albumin group has a flatter curve for the first 6–10 months, which means more albumin
patients are surviving during early follow-up.
The albumin group has survival events (deaths) occurring later on the timeline.
Even if more albumin patients died, they lived longer before dying.

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 80

CONCLUSIONS
 CONCLUSIONS

CONCLUSIONS
 This prospective observational study evaluated the impact of albumin infusion on
clinical outcomes, laboratory parameters, and quality of life in patients with
hepatocellular carcinoma (HCC). The findings indicate that albumin administration
may offer supportive clinical benefits, particularly in patients with moderate to severe
liver dysfunction.

 Patients in the albumin group exhibited improvements in certain key parameters,

including stabilization of serum creatinine and INR levels, reduction in AST and AFP
values, and enhanced control of ascites. Importantly, a statistically significant
improvement in quality-of-life scores was observed over time in the albumin group,
suggesting a positive effect on patient-reported well-being. While the non-albumin
group also showed some favorable changes, they experienced a significant rise in
creatinine and INR, indicating a trend toward worsening renal and coagulation status.

 Although the difference in overall survival between the two groups was not statistically
significant, the Kaplan–Meier survival analysis revealed a trend toward delayed
mortality in patients who received albumin. This suggests that albumin may help
maintain clinical stability and delay disease progression in selected individuals.

 Overall, the study highlights the potential role of albumin as a supportive adjunct in the
management of HCC, especially in those with decompensated liver function. However,
given the limited sample size and observational design, these findings should be
interpreted with caution. Further large-scale, controlled trials are necessary to validate
the clinical utility and long-term benefits of albumin infusion in this patient population.

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 81

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56. Chie W, et al. International validation of EORTC QLQ-HCC18. Hepatology. 2012;55.

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Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 86

APPENDIX INSTITUTIONAL COMMITTEE APPROVAL LETTER

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 87

APPENDIX INSTITUTIONAL COMMITTEE APPROVAL LETTER

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 88

APPENDIX DATA COLLECTION FORM

TO ASSESS THE ROLE OF ALBUMIN INFUSION ON

QUALITY OF LIFE IN PATIENTS WITH HEPATOCELLULAR
CARCINOMA - A PROSPECTIVE STUDY
[Link] REDDY COLLEGE OF PHARMACY,
Mehdipatnam, Hyderabad.
Department of Pharmacy Practice

Patient ID:
Date of birth: (dd/mm/yyyy) Age: (Years)
Sex: Male: Female:
Date of visit: (dd/mm/yyyy)

Etiology NAFLD:_____ ALD:_____ HEP B:_____ HEP C:_____

Others:_____

Current
Medications
Comorbidities

Liver Function Test Assessment:

Child-pugh score Class A ____ Class B ____ Class C ____
ALBI score
MELD score
Performance status (ECOG) 0 ___
1 ___
2 ___

Tumor Marker

AFP

PIVKA-II

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 89

APPENDIX DATA COLLECTION FORM

Treatment Details:

Systemic Therapy Sorafenib

Date of starting therapy
Levatinib ___/___/___
Date of Ending therapy
Others (Specify) ___/___/___
Albumin Infusion Freq ____ Dose ____
Received: Yes/No

Locoregional Therapy TACE: Date of LRT

(LRT) TARE: ____/___/___

Follow-Up Assessments

Parameter Baseline 1 Month 3 Months

Hb
TLC
Serum Albumin (g/dl)
Total Bilirubin (mg/dl)
ALT/AST (U/L)
Creatinine (mg/dl)
INR
Na
AFP (ng/ml)
QoL (EORTC QLQ-
HCC18)
Complications:
 Ascites Grade 1/2/3 Grade 1/2/3 Grade 1/2/3
 Kidney Injury Yes/No Yes/No Yes/No
 Hyponatremia Yes/No Yes/No Yes/No

Outcomes

Parameter

Improvement in QoL (EORTC QLQ- Yes/No

HCC18)
Control of Ascites Yes/No
AKI Yes/No
Hyponatremia Yes/No
Survival Yes/No
Infection Incidence (source/site) Yes/No
Hospitalization indication Yes/No

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 90

APPENDIX INFORMED CONSENT FORM

INFORMED CONSENT DOCUMENT (ICD)

[Written subject information sheet & consent form]

Study Title: To assess the role of Albumin infusion on Quality

of life in patients with Hepatocellular Carcinoma

Language: English

Subject Identification
Subject full name in BLOCK LETTERS:

Subject identification (ID) No: Date of Birth / Age at the time of consent:

Study Doctor

Name of the Investigator(s): 1. Dr. Anand V Kulkarni

(anandvk90@[Link])
Email ID:

Name of the sub-investigator(s) / Guide: 1. Dr. Santhosh Reddy Satti

Email ID: (drsanthoshreddy01@[Link])

2. Dr. Lalitha Devi

(lalithapharmacology@[Link])

3. Fazila Shakeel Ahmed

(fazila.shakeel02@[Link])

4. Saniya Khatoon
(saniyakhan2713@[Link])

5. Ifath Fatima
(ifathfatima1234@[Link])

6. Zeba Nureen
(zebanureen6102@[Link])

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 91

 APPENDIX INFORMED CONSENT FORM

Address(s) of the study site:

Department of Hepatology, AIG hospitals, Mindspace road, Gachibowli, Hyderabad.
Telephone: +91 4042444222

1) Participation.
We are approaching you with a request to participate in the study because you are diagnosed
with Hepatocellular Carcinoma. Before you can take part in this study, it is important that you
understand what the study involves. Please read this information carefully and ask any
questions that you might have. You will be included in the study only after you give consent
to take part in the study.

2) Purpose and Aim of the Study.

To assess the role of Albumin infusion on Quality of life in patients with Hepatocellular
Carcinoma.

3) The approximate number of participants and the expected duration of your

participation in the study:
Total Number of patients included in the study are 100-150.
Duration of the study is 1 year.

4) What other treatment options do I have?

N/A

5) Study Procedure / Methodology.

We have found you eligible for the study and there by seeking your consent to participate by
explaining the study procedure.
Once you are enrolled, we will take detailed clinical history using Questionnaires and record
the answers.

6) Role of the Patient:

Patient will be required to provide accurate information about their medical history along
with any complications.

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 92

 APPENDIX INFORMED CONSENT FORM

They will need to answer the Questionnaire [European Organization for Research and
Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18-question
module (EORTC QLQ-HCC18)].

7) Follow-up / Duration of the study.

After you consent to participate in the study and you are enrolled, you will be under the study
supervision for 1 year, you will have to visit the center as per the schedule.
If for any reason you are not able to visit the hospital we will reach you by telephone.

8) What are the expected benefits of this study?

We can assess the safety and efficacy of Albumin infusion for future reference.

You may or may not benefit from participating in this study, but the knowledge gained may
benefit others.

9) Your responsibilities.
Completely read the consent form and ask the Principal Investigator (PI) any questions you
may have. You should understand what will happen to you during the study before you agree
to participate. You should talk to the Principal Investigator (PI; the person in charge of the study)
if you want to stop being part of the research study. You should report to the PI immediately about
any problems you may be having with the study procedure/device. You should fulfill the
responsibilities of participation as described on the consent forms unless you are stopping your
participation in the study. You can ask for the results of the study, if you want them. You should
keep a copy of the consent form for your records

10) Voluntary Participation / Withdrawal from the Study

Your participation in this study is entirely voluntary. It is up to you to decide whether to take
part or not. Even if you do decide to take part, you are free to leave the study at any time
without giving a reason. This will not affect your future medical care in any way. Furthermore,
your study doctor may withdraw you from the study if he/she feels this is in your best interest,
or in case of stopping the study early. If you decide to withdraw your consent to participate
in the study, your study doctor will ask your permission to perform the final evaluation and
to collect the data through a report form. If you do not agree, no new data on you will be
added to the database.

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 APPENDIX INFORMED CONSENT FORM

Your doctor, the sponsor of the study or designee, may end your participation in this study at
any time without your consent. The possible reasons for ending your participation: if the
study treatment offers you little or no future benefits or if you develop severe or life-
threatening side effects. You will be discontinued from the study if you fail to follow
directions for participating in the study.

11) Permission for Review of Records, Confidentiality and Access to Records

After seeking permission from you, the study doctor or research staff will collect information
about you. This information called data will be entered without your name, on a report form.
In all these report forms a code will replace your name. All the data collected will be kept
confidential. Authorized personnel will enter the data into the investigator’s / sponsor’s case
report form or computer database. The data collected will be used for the evaluation of the
study and may be used in the future in related or other studies. This data may also be used for
the purpose of publication and presentations at Scientific platforms.

The data may be submitted to health authorities for registration purposes. Health authorities,
Indian Council of Medical Research (ICMR) and like, Institutional Ethics Committee (IEC)
/ Institutional Review Board (IRB) or other persons required by law may review the data
provided.

To make sure that the data collected from you is correct, it is necessary for the sponsor or
national / international authorities to directly compare them with your medical record. Such
checks will only be done by qualified and authorized personnel. While all reasonable efforts
will be made to keep the data confidential, absolute confidentiality cannot be guaranteed.

12) Questions/Information.

(i) If you or your representative(s) have any questions regarding the study or in case of
study related injuries, you should contact your study doctor.

Name of the investigator/study doctor: Dr. Anand V Kulkarni

Telephone: +91 8553322434

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APPENDIX INFORMED CONSENT FORM

(ii) If you or your representative(s) have any questions regarding your subject rights as they
relate to the study, you should contact the following personnel as allowed by local
regulation and IRB/IEC policy,

Name of the IEC Personnel: Dr. Deepa Shukla

Telephone: +91 9953900117

(iii) If you seek emergency care, or if hospitalization is required, please inform the treating
doctor that you are participating in a clinical trial.
(iv) If any new information becomes available during the study that may affect your
willingness to participate, you will be informed.

Informed Consent Declaration

Date: _____________
Subject Name: ______________________________________________ Sex: __________
S/o, W/o., D/o: _____________________________________________________________
Subject ID: _______________________________________________________________
Date of birth/Age at the time of consent: _______________________________________
Address of the subject: _______________________________________________________
___________________________________________________________________________
Subject contact number:______________________________________________________
Qualification: ______________________________________________________________
Occupation: Student / Self-employed / Service / Housewife / Other (Tick as appropriate)
If other, kindly mention: _____________________

● I have been provided with the details of the known or foreseeable side effects and risks of
the research medication and study procedures that I may receive.

● I understand I am free to accept or refuse my participation at any time without giving a

reason. My decision to accept or refuse my participation will have no effect on my
continuing treatment. I understand that I am free to discontinue my participation at any
time without giving a reason. My decision to discontinue my participation will have no

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APPENDIX INFORMED CONSENT FORM

effect on my continuing treatment. I will keep all my rights to treatment and alternative
therapy.

● I agree that data collected for the study will be used for the purpose described above,
including transferring data to the case report form or database and processing and archiving
by AIG in a coded form with respect to the confidentiality of my data.

● I agree that direct access to my medical records may be given to authorized persons
representing national and international authorities. These authorities may include the local
regulatory authorities or Institutional Ethics Committee (IEC)/Institutional Review Boards
(IRB’s).

● I understand that my study records can be forwarded to my primary physician if I request

my study doctor to do so.

● I will not lose any rights that I have under the law by signing and dating this form.

● I have read and understood the information presented in this informed consent form. I have
been given the opportunity to ask questions, and they have been answered.

● I will receive a signed and dated copy of this Informed Consent Form.

Serial Particulars Initial in

No. box
1. I confirm that I have read and understood the information sheet dated
__________ (dd/mm/yyyy) for the above study and had the
opportunity to ask questions. My questions have been answered
satisfactorily.
2. I understand that my participation in the study is voluntary and that I
am free to withdraw at any time, without giving any reason, without
my medical care or legal rights being affected.
3. I understand that the ethics committee and the regulatory authorities
will not need any permission to look at my health records both in

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 APPENDIX INFORMED CONSENT FORM

respect of the present study or any further research that may be

conducted in relation to it even if I withdraw from the trial. I agree
with this access. However, I understand that my identity will not be
revealed in any information released to third parties or published.
4. I agree not to restrict the use of any data or result that arises from this
study provided such use is only for the scientific purpose(s).
5. I agree to take part in the above study, allow access to my data in the
study, and I agree to co-operate and inform unexpected or unusual
symptoms experienced during the study. For the duration of the study,
I will notify the investigator of any other medical treatments that may
be necessary to undergo. I received a copy of this consent form.
6. All the above has been explained to me in a language I know and I
understand.

____________________ _____________________ _________________

Name of the subject Signature /thumb impression Date (DD/MM/YYYY)
of the subject

_____________________ ___________________ __________________

Name of the legally Signature/thumb impression Date (DD/MM/YYYY)
acceptable representative of the legally acceptable representative
(Mention relationship with
the subject)

________________________ ______________________ ________________

Name of the investigator Signature of the investigator Date (DD/MM/YYYY)

If the subject / legally acceptable representative cannot read:

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APPENDIX INFORMED CONSENT FORM

__________________________ _____________________ ______________

Name of impartial witness 1 Signature of the impartial Date (DD/MM/YYYY)
witness 1

___________________________ ___________________ ______________

Name of impartial witness 2 Signature of the impartial Date (DD/MM/YYYY)
witness 2

Nominee(s):

Name: ____________________________________________________________________

Address___________________________________________________________________

Telephone if any: ___________________________________________________________

Legally accepted representative (LAR) [in case of signature obtained from LAR]:

Name: ____________________________________________________________________

Address___________________________________________________________________

Telephone if any: ___________________________________________________________

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APPENDIX INFORMED CONSENT FORM

Impartial witness(es) if any:

Name: ____________________________________________________________________

Address___________________________________________________________________

Telephone if any: ___________________________________________________________

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 99

APPENDIX EORTC QLQ HCC-18

EORTC QLQ – HCC18

Patients sometimes report that they have the following symptoms or problems. Please indicate
the
extent to which you have experienced these symptoms or problems during the past week. Please
answer by circling the number that best applies to you.

During the past four weeks: Not A Quite Very

at all little a bit much
1. Did you feel thirsty? 1 2 3 4
2. Have you had problems with your sense of taste? 1 2 3 4
3. Have you lost muscle from your arms or legs? 1 2 3 4
4. Have you had abdominal swelling? 1 2 3 4
5. Have you been concerned by the appearance of your 1 2 3 4
abdomen?
6. Have you been concerned by your skin or eyes being 1 2 3 4
yellow (jaundiced) ?
7. Have you had itching? 1 2 3 4
8. Have you had pain in your shoulder? 1 2 3 4
9. Have you had abdominal pain? 1 2 3 4
10. Have you had fevers? 1 2 3 4
11. Have you had chills? 1 2 3 4
12. Have you worried about getting enough nourishment? 1 2 3 4

13. Have you felt full up too quickly after beginning to eat? 1 2 3 4

14. Have you worried about your weight being too low? 1 2 3 4

15. Have you been less active than you would like to be? 1 2 3 4

16. Have you found it difficult to finish things? 1 2 3 4

17. Have you needed to sleep during the day? 1 2 3 4
During the past week:
18. Has the disease or treatment had any effect on your sex 1 2 3 4
life?

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 100
 CO-CURRICULAR ACTIVITIES

G. PULLA REDDY COLLEGE OF PHARMACY, HYDERABAD

DEPARTMENT OF PHARMACY PRACTICE

NAME OF THE STUDENT: FAZILA SHAKEEL AHMED

ROLL NO. : 170120882009
CLASS/YEAR : PHARM D V YEAR
ACADEMIC YEAR : 2024-2025
Date of Participation Date of Participation E-certificates/Acknowledgement
21st December 2024 Participated and
Presented Poster
Scientific Paper in One
Day Seminar on
“Innovations in
Pharmaceutical
Research-24" on the
topic “Albumin
Dynamics in HCC”

14th June 2025 Certificate of

Appreciation on
Donating Blood

11th February 2024 Awarded First Prize in

“Badminton Singles”
tournament at SUCP

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 101
 CO-CURRICULAR ACTIVITIES

11th February 2024 Awarded First Prize in

“Badminton Singles”
tournament at SUCP

28th February 2024 Certificate of

Appreciation for
participating in
“Pharmaceutical
Experiments
Demonstration” on
occasion of National
Science day Celebration

17th August 2024 Certificate on

successfully completing
the First Aid & Basic
Life Support (BLS)
training conducted by
AIG Hospitals

22nd July 2025 Successfully completed

the course in “Pediatric
Life Support (PALS)” by
Alison.

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 102
 CO-CURRICULAR ACTIVITIES

23rd April 2025 Successfully completed

the course in “HACCP
Food Safety System for
Restaurants and other
Catering Services”

22nd July 2025 Successfully completed

the course in
“Medication
Management and
Administration” by
Alison.

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 103
 CO-CURRICULAR ACTIVITIES

G. PULLA REDDY COLLEGE OF PHARMACY, HYDERABAD

DEPARTMENT OF PHARMACY PRACTICE

NAME OF THE STUDENT: SANIYA KHATOON

ROLL NO. : 170120882020
CLASS/YEAR : PHARM D V YEAR
ACADEMIC YEAR : 2024-2025
Date of Date of Participation E-certificates/Acknowledgement
Participation
5th August 2024 Completed One Month
to 4th September Hands on Training Course
2024 “SAS Programming for
Clinical, Pharmaceutical and
Healthcare Data Analysis”
conducted by G. Pulla Reddy
College of Pharmacy in
association with Clinsights,
Hyderabad.

19th April 2025 Awarded First Prize in

“Throwball” during 29th
College Annual Day
Celebration at G. Pulla
Reddy College of Pharmacy

5th June to 7th Certificate of Poster

June 2024 presentation titled “Rare
diseases in India” in the
scientific session of the three
day INDO-US SUMMIT on
“Innovation in Pharma
Education”

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 104
 CO-CURRICULAR ACTIVITIES

17th August 2024 Certificate on successfully

completing the First Aid &
Basic Life Support (BLS)
training conducted by AIG
Hospitals

27th February Certificate of Appreciation

2024 for participating in “Video
presentation” on the theme
“Indigenous Technologies for
Viksat Bharat” on National
Science Day Celebrations

27th April 2024 Participation certificate at the

Healthitude 2024 Inter
college Health fest organized
by Post Graduate Diploma in
Management

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 105
 CO-CURRICULAR ACTIVITIES

G. PULLA REDDY COLLEGE OF PHARMACY, HYDERABAD

DEPARTMENT OF PHARMACY PRACTICE

NAME OF THE STUDENT: ZEBA NUREEN

ROLL NO. : 170120882019
CLASS/YEAR : PHARM D V YEAR
ACADEMIC YEAR : 2024-2025
Date of Participation Date of Participation E-certificates/Acknowledgement
7th January 2025 Participated as delegate
in AIG Artificial
Intelligence in
Healthcare 2.0

24th June 2025 Participated in the

International Clinical
Trials Day Celebration
organized by Yashoda
Hospitals

5th August 2024 to 4th Completed One Month

September 2024 Hands on Training
Course “SAS
Programming for
Clinical,
Pharmaceutical and
Healthcare Data
Analysis” conducted by
G. Pulla Reddy College
of Pharmacy in
association with
Clinsights, Hyderabad.

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 106
 CO-CURRICULAR ACTIVITIES

24th August 2024 Certificate of

Recognition for
successfully registering
on My Bharat and
taking stride towards
Viksit Bharat

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 107
 CO-CURRICULAR ACTIVITIES

G. PULLA REDDY COLLEGE OF PHARMACY, HYDERABAD

DEPARTMENT OF PHARMACY PRACTICE

NAME OF THE STUDENT: IFATH FATIMA

ROLL NO. : 170120882006
CLASS/YEAR : PHARM D V YEAR
ACADEMIC YEAR : 2024-2025
Date of Participation Date of Participation E-certificates/Acknowledgement
5th August 2024 to 4th Completed One Month
September 2024 Hands on Training
Course “SAS
Programming for
Clinical, Pharmaceutical
and Healthcare Data
Analysis” conducted by
G. Pulla Reddy College
of Pharmacy in
association with
Clinsights, Hyderabad.

21st December 2024 Participated and

Presented Poster
Scientific Paper in One
Day Seminar on
“Innovations in
Pharmaceutical
Research-24" on the
topic “Role of
Antioxidants in AFLD”

11th March 2024 Certificate for serving as

a Volunteer on “One day
conference on Pharmacy
Practice”

Dept. of pharmacy practice, G. Pulla Reddy College Of Pharmacy, Hyderabad Page 108