UNDERSTANDING HEMOCHROMATOSIS: IMPLICATIONS FOR

PANCREATIC HEALTH

BY

OKOTO HARMONY ONORIODE

MLS/19/2036

DEPARTMENT OF MEDICAL LABORATORY SCIENCE

HISTOPATHOLOGY/CYTOLOGY DEPARTMENT

SUPERVISOR: DR. EMMANUEL ONUOHA

COORDINATOR: DR. EZE RICHARD
 UNDERSTANDING HEMOCHROMATOSIS: IMPLICATIONS FOR

PANCREATIC HEALTH

BY

OKOTO HARMONY ONORIODE

MLS/19/2036

A SEMINAR REPORT SUBMITTED IN PARTIAL FULFILMENT OF

THE REQUIREMENTS FOR THE AWARDS OF BACHELOR OF
MEDICAL LABORATORY SCIENCE (B.MLS) IN DEPARTMENT OF
MEDICAL LABORATORY SCIENCE (HISTOPATHOLOGY
/CYTOLOGY DEPARTMENT) FACULTY OF HEALTH SCIENCES
MADONNA UNIVERSITY, ELELE CAMPUS RIVERS STATE.

COURSE TITLE: SEMINAR

COURSE CODE: MLS 584

SUPERVISOR: DR. ONUOHA, EMMANUEL

COORDINATOR: DR. EZE, RICHARD

MAY, 2024
 DEDICATION

I dedicate this work to Almighty God for his mercy and love, and also to my parents Mr. and

Mrs. Okoto, for their love, care and endless support throughout my stay in Madonna

University

iii
 DECLARATION

This is to declare that this seminar work titled “Understanding Hemochromatosis:

Implications For Pancreatic Health” was carried out by OKOTO HARMONY

ONORIODE in Medical Laboratory Science, Madonna University, Elele, Rivers State.

References made to published literatures have been fully acknowledged.

--------------------------------- -------------------------------

Signature Date

iv
 ACKNOWLEDGMENTS

My immeasurable gratitude goes out to my supervisor Dr. Onuoha, Emmanuel for his

guidance. He has been a true teacher to me and I am grateful for his supervision, reviews and

extensive support that this seminar work to fulfilment.

Special thanks to the head of department Dr. (Sr.) Arvin Nwakulite and the lecturers of

Medical Laboratory Science, Madonna University for their sound and flawless training and

counselling and for leading me in this academic pursuit.

Innumerable thanks to my parents Mr. and Mrs. Okoto and my sisters for being the

unshakable pillar behind my success and for the support and encouragement throughout my

stay in the university.

My gratitude also goes out to my friends for their endless support and words of

encouragements. May God bless you all.

v
 CERTIFICATION

This is to certify that the seminar work titled “UNDERSTANDING

HEMOCHROMATOSIS : IMPLICATIONS FOR PANCREATIC HEALTH” was

carried out by Okoto, Harmony Onoriode with registration number MLS/19/2036 under

the supervision of Dr. Emmanuel Onuoha in the Department of Medical Laboratory

Science, Madonna University, Elele, Rivers State.

-------------------------------- -------------------------

DR EMMANUEL ONUOHA DATE

(SUPERVISOR)

------------------------------------- -----------------------------

DR EZE RICHARD DATE

(COORDINATOR)

------------------------------------- ------------------------------

DR. (SR.) ARVIN NWAKULITE DATE

(HEAD OF DEPARTMENT)

vi
 TABLE OF CONTENTS

Cover page i
Tittle page ii
Dedication iii
Declaration iv
Acknowledgment v
Certification vi
Table of content vii
List of figures viii
Summary 1
CHAPTER ONE: INTRODUCTION
1.0 Introduction` 2
1.1 Background 2
CHAPTER TWO: LITERATURE REVIEW
2.1 Types of Hemochromatosis 4
2.2 Epidemiology of Hemochromatosis 5
2.3Pathophysiology of Hemochromatosis 6
2.4Etiology of Hemochromatosis 7
2.5Pancreatic Implications of Hemochromatosis 8
2.6Clinical Manifestations of Hemochromatosis 18
2.7Diagnosis of Hemochromatosis 19
2.8Treatment of Hemochromatosis 22
Conclusion 24
Recommendation 25
Reference 26
LIST OF FIGURES PAGES

Figure 1: Normal anatomy of pancreas of human being 14

Figure 2: Showing Secondary iron overload inducing chronic pancreatitis and ferroptosis

of acinar cells in mice 15

 SUMMARY
Hemochromatosis is a genetic disorder characterised by excessive absorption of dietary iron
leading to iron overload in the body. Hemochromatosis can lead to damage of organs such as;
heart, liver, pancreas, thyroid, joint, skin, gonads and pituitary. It is classified into; Primary
hemochromatosis is the most common form of hemochromatosis. Secondary iron overload
which usually arises from causes such as transfusion, hemolysis, or excessive parenteral
and/or dietary consumption of iron. Genetic factor is the most common risk factor of
hemochromatosis, others may include family history, ethnicity, and gender. Early detection
and management through regular blood removal (phlebotomy) can help control iron levels
and prevent complications. In hemochromatosis, excess iron accumulation can affect the
pancreas. Iron deposition in the pancreas may lead to damage of pancreatic tissue and impair
its normal function. This can result in conditions such as diabetes mellitus, which is a known
complication of hemochromatosis. The pancreas plays a crucial role in regulating blood sugar
levels, and disruption caused by iron overload can contribute to the development of diabetes
in individuals with hemochromatosis. Regular monitoring and management of iron levels are
essential to minimize the impact on various organs, including the pancreas. Understanding
the genetic basis of hemochromatosis is crucial for identifying individuals at risk and
implementing early interventions to prevent organ damage. Exploring its effects on various
organs, with a specific focus on the pancreas, helps in devising targeted strategies for
diagnosis, management, and improving the overall quality of life for individuals affected by
this disorder.

1
 CHAPTER ONE

1.0 INTRODUCTION

1.1 BACKGROUND

The pancreas plays a vital role in coordinating and regulating digestion and nutrient

metabolism, and does so via endocrine and exocrine processes. Insulin and glucagon are

produced within the endocrine pancreas to not only achieve glucose homeostasis, but regulate

protein and fat metabolism. Enzymes and zymogens are secreted in alkaline pancreatic fluid

to aid digestive function. This article looks at how the pancreas achieves such precise

synthetic and secretory functions, and reviews the physiology of the secreted hormones and

enzymes. (Jennifer E. Cade et al, 2017)

The normal human pancreas contains 1–2 million islets, each of which is an aggregate of tens

to thousands of cells. The islets are ovoid in shape and are scattered throughout the pancreas,

although are more numerous in the pancreatic tail. There are now known to be at least five

major secretory cell types in each islet of Langerhans – α, β, δ, F and ε cells. Pancreatic α

cells principally secrete glucagon, and comprise approximately 35% of islet cells. Pancreatic

β cells are most (Jennifer E. Cade et al, 2017)

The functional unit of the exocrine pancreas is formed by the acinus. This structure is a

collection of wedge-shapes secretory cells (usually less than 100) that are organized in a

round ‘berry’ shape with a central cavity within. These cells secrete fluid laden with proteins,

zymogens (enzyme precursors) and enzymes that then drains from the central cavity to a

duct. This is named an intercalated duct and is comprised of flattened cuboidal epithelial

cells. (Jennifer E. Cade et al, 2017)

Hemochromatosis, is defined as systemic iron overload of genetic origin, caused by reduction

in the concentration of the iron regulatory hormone hepcidin, or a reduction in hepcidin–

2
ferroportin binding. Hepcidin regulates the activity of ferroportin, which is the only identified

cellular iron exporter. The most common form of haemochromatosis is due to homozygous

mutations (specifically, the C282Y mutation) in HFE, which encodes hereditary

haemochromatosis protein. (Pierre Brissot et al, 2018)

Cellular iron excess in HFE and non-HFE forms of haemochromatosis is caused by increased

concentrations of plasma iron, which can lead to the accumulation of iron in parenchymal

cells, particularly hepatocytes, pancreatic cells and cardiomyocytes. Diagnosis is noninvasive

and includes clinical examination, assessment of plasma iron parameters, imaging and

genetic testing. (Pierre Brissot et al, 2018)

3
 CHAPTER TWO

LITERATURE REVIEW.

2.1 TYPES OF HEMOCHROMATOSIS

2.1.1 PRIMARY/HEREDITARY HEMOCHROMATOSIS

Hereditary hemochromatosis (HH) is defined as an inherited iron overload disorder

characterized by excessive absorption of iron, due to deficiency of hepcidin.

There are 4 main types of HH that have been categorized based on which proteins involved in

iron homeostasis are affected. (Kowdley et al 2019)

a) Type 1 hereditary hemochromatosis is the most frequent inherited form of iron overload

The most common mutation is a G to A transition at nucleotide 845 of the HFE gene,

resulting in a cysteine to tyrosine substitution at amino acid 282 (C282Y), referred to as type

1a. Another known genetic subtype is the H63D mutation, which does not cause significant

iron overload but may act as a cofactor for phenotypic expression of iron overload, primarily

in combination with C282Y. This genotype of C282Y/H63D is classified as HH type 1b or

compound heterozygote. The prevalence of this mutation is approximately 2%–4% among

patients of northern European origin. (Kowdley et al 2019)

b) Type 2 hereditary hemochromatosis, also called juvenile hemochromatosis, is associated

with mutations in the HJV (hemojuvelin) gene (type 2A) or the hepatic antimicrobial protein

(HAMP) gene (type 2B), respectively, leading to hepcidin deficiency. This mutation tends to

lead to the most severe form of primary iron overload, primarily occurring in younger

individuals (Kowdley et al 2019)

c)Type 3 HH is associated with mutations in the transferrin receptor 2 (TFR2) gene, also

leading to hepcidin deficiency. (Kowdley et al 2019)

d)Type 4A hereditary hemochromatosis, also known as ferroportin disease, is the only

autosomal dominant form of hemochromatosis due to mutations in the ferroportin1 gene

4
(SLC40A1). In this condition, the production of hepcidin is normal, but the export function of

ferroportin1 is diminished, leading to intracellular iron retention with low levels of plasma

iron and normal or low levels of TS but elevated SF levels. The spleen is the most affected

organ in type 4A Hereditary Hemochromatosis, because of high ferroportin1 activity at the

level of macrophages. Type 4B hereditary hemochromatosis is a form of iron overload due to

resistance of Ferroportin1 to hepcidin. (Kowdley et al 2019)

2.2.2. Secondary hemochromatosis

Secondary iron overload results from excess absorption of iron, repeated blood transfusions,

or excess oral intake, typically in patients with disorders of erythropoiesis. Consequences can

include systemic symptoms, liver disorders, cardiomyopathy, diabetes, erectile dysfunction,

and arthropathy. Diagnosis is by elevated serum ferritin, iron, and transferrin saturation

levels. Treatment is usually by iron chelation Secondary iron overload typically occurs in

patients who have: Hemoglobinopathies (eg, sickle cell disease, thalassemia, sideroblastic

anemias), Congenital hemolytic anemias (eg, hemoglobinopathies, hereditary spherocytosis),

Myelodysplasia. (Hamilton, 2022)

2.2.3 Neonatal Hemochromatosis

Neonatal hemochromatosis is a rare condition that causes neonatal liver failure, frequently

resulting in fetal loss or neonatal death. It is thought that most cases of neonatal

hemochromatosis are caused by gestational alloimmune liver disease (GALD), with neonatal

hemochromatosis being a phenotype of GALD rather than a disease process. Extrahepatic

siderosis in the pancreas, myocardium, thyroid and minor salivary gland is a characteristic

feature of neonatal hemochromatosis. (Govind BC et al, 2022)

2.2 EPIDEMIOLOGY OF HAEMOCHROMATOSIS

The prevalence of HFE-related HH has been observed to be similar in the United States,

Europe, and Australia, of approximately 1 case in 200–400 persons. The highest prevalence

5
exists in people of Irish and Scandinavian origin, whereas the lowest is among those of

African descent. Additionally, the prevalence of HFE-related HH is lower among whites who

are not of northern European descent, such as those of eastern European or Mediterranean

origin. The prevalence among non-Hispanic whites in the United States is 1 in 300. The

incidence of HH varies from 1.5 to 3 cases per 1,000 persons up to 1 case per 200–400

persons, although the true incidence is difficult to determine as it can only be assessed in

newborn screening studies. According to a meta-analysis using a pooled cohort of 127,613

individuals across Europe, the allelic frequency of C282Y in the general population

approaches 6.2%. The percentage of patients with phenotypic HH attributed to C282Y

homozygosity, however, approaches 80.6%, according to a meta-analysis of 2,802 patients.

The homozygous C282Y mutation is significantly more prevalent among non-Hispanic

whites (0.44%) compared with Native Americans (0.11%), Hispanics (0.027%), African

Americans (0.014%), Pacific Islanders (0.012%), or Asians (0.000039%). (Kowdley et al

2019)

2.3 PATHOPHYSIOLOGY OF HEREDITARY HEMOCHROMATOSIS

Normal total body iron content is about 2.5 g in women and 3.5 g in men. Because symptoms

may be delayed until iron accumulation is excessive (eg, > 10 to 20 g), hemochromatosis may

not be recognized until later in life, even though it is an inherited abnormality. In women,

clinical manifestations are uncommon before menopause because iron loss due to menses

(and sometimes pregnancy and childbirth) tends to offset iron accumulation. (Hamilton,

2022)

The mechanism for iron overload in both HFE and non-HFE hemochromatosis is increased

iron absorption from the gastrointestinal tract, leading to chronic deposition of iron in the

tissues. Hepcidin, a liver-derived peptide, is the critical control mechanism for iron

absorption. Hepcidin is normally up-regulated when iron stores are elevated and, through its

6
inhibitory effect on ferroportin (which participates in iron absorption), it prevents excessive

iron absorption and storage in normal people. Hemochromatosis types 1 through 4 share the

same pathogenic basis (e.g., lack of hepcidin synthesis or activity) and key clinical features.

(Hamilton, 2022)

In general, tissue injury appears to result from reactive free hydroxyl radicals generated when

iron deposition in tissues catalyzes their formation. Other mechanisms may affect particular

organs (e.g., skin hyperpigmentation can result from increased melanin as well as iron

accumulation). In the liver, iron-associated lipid peroxidation induces hepatocyte apoptosis,

which stimulates Kupffer cell activation and release of pro-inflammatory cytokines. These

cytokines activate hepatic stellate cells to produce collagen, resulting in pathologic

accumulation of liver fibrosis and risk of hepatocellular carcinoma. (Hamilton, 2022)

2.4 ETIOLOGY OF HEMOCHROMATOSIS

2.4.1 Type 1 hereditary hemochromatosis

Type 1 is classic hereditary hemochromatosis, also termed HFE-related hemochromatosis.

More than 80% of cases are caused by the homozygous C282Y mutation or the C282Y/H63D

compound heterozygous mutation. Homozygous H63D mutations occur rarely and have the

same phenotype as homozygous C282y cases. The disorder is autosomal recessive, with a

homozygous frequency of 1:200 and a heterozygous frequency of 1:8 in people of northern

European ancestry. The C282Y and H63D mutations are uncommon among people with

African ancestry and rare among people with Asian ancestry. Of patients with clinical

features of hemochromatosis, 83% are homozygous. However, for unknown reasons,

phenotypic (clinical) disease is much less common than predicted by the frequency of the

gene (ie, many homozygous people do not manifest the disorder. (Hamilton, 2022)

2.4.2 Type 2 hereditary hemochromatosis:

7
Type 2 hereditary hemochromatosis (juvenile hemochromatosis) is a rare autosomal recessive

disorder caused by mutations in the HJV gene that affect the transcription protein

hemojuvelin, or mutations in the HAMP gene, which directly codes for hepcidin. It often

manifests in adolescents. (Hamilton, 2022)

2.4.3. Type 3 hereditary hemochromatosis:

Mutations in transferrin receptor 2 (TFR2) gene that codes for a protein that appears to

control saturation of transferrin, can cause a rare autosomal recessive form of

hemochromatosis. (Hamilton, 2022)

2.4.4 Type 4 hereditary hemochromatosis:

Type 4 hereditary hemochromatosis (ferroportin disease) occurs largely in people of southern

European ancestry. It results from an autosomal dominant mutation in the SLC40A1 gene and

affects the ability of ferroportin to bind hepcidin. (Hamilton, 2022)

2.4.5 Transferrin and ceruloplasmin deficiency

In transferrin deficiency (hypotransferrinemia or atransferrinemia), absorbed iron that enters

the portal system not bound to transferrin is deposited in the liver. Subsequent iron transfer to

sites of red blood cell production is reduced because of transferrin deficiency.

In ceruloplasmin deficiency (aceruloplasminemia), lack of ferroxidase causes defective

conversion of Fe2+ to Fe3+; such conversion is necessary for binding to transferrin.

Defective transferrin binding impairs the movement of iron from intracellular stores to

plasma transport, resulting in accumulation of iron in tissues. (Hamilton, 2022)

2.5 PANCREATIC IMPLICATIONS OF HEMOCHROMATOSIS:

8
The pancreas is a composite organ, which has exocrine and endocrine functions. The

endocrine portion is arranged as discrete islets of Langerhans, which are composed of five

different endocrine cell types (alpha, beta, delta, epsilon, and upsilon) secreting at least five

hormones including glucagon, insulin, somatostatin, ghrelin, and pancreatic polypeptide,

respectively. (El Sayed et al, 2023)

Insulin

Source: Beta cells of islets of the pancreas.

Synthesis: Insulin is a peptide hormone. The insulin mRNA is translated as a single-chain

precursor called preproinsulin, and removal of its signal peptide during insertion into the

endoplasmic reticulum generates proinsulin. Within the endoplasmic reticulum, proinsulin is

exposed to several specific endopeptidases, which excise the C peptide (one of three domains

of proinsulin), thereby generating the mature form of insulin. Insulin is secreted from the cell

by exocytosis and diffuses into islet capillary blood. C-peptide is also secreted into the blood

in a 1:1 molar ratio with insulin. Although C-peptide has no established biological action, it is

used as a useful marker for insulin secretion. (El Sayed et al, 2023)

Transport: insulin circulates entirely in unbound form (T1/2 = 6 min).

Main Target cells: hepatic, muscle and adipocyte cells (i.e., cells specialized for energy

storage).

Mechanism of action: Insulin binds to a specific receptor tyrosine kinase on the plasma

membrane and increases its activity to phosphorylate numerous regulatory enzymes and other

protein substrates. (El Sayed et al, 2023)

Regulation of its secretion:

Plasma glucose level is the main regulator of insulin secretion. The change in the

concentration of plasma glucose that occurs in response to feeding or fasting is the main

9
determinant of insulin secretion. Modest increases in plasma glucose level provoke a marked

increase in plasma insulin concentration. Glucose is taken up by beta cells via glucose

transporters (GLUT2). The subsequent metabolism of glucose increases cellular adenosine

triphosphate (ATP) concentrations and closes ATP-dependent potassium (KATP) channels in

the beta cell membrane, causing membrane depolarization and an influx of calcium.

Increased calcium intracellular concentration results in an increase of insulin secretion. (El

Sayed et al, 2023)

Increased plasma amino acid and free fatty acid concentrations induce insulin secretion as

well.

Glucagon is also known to be a strong insulin secretagogue. (El Sayed et al, 2023)

Physiological functions:

Insulin plays an important role to keep plasma glucose value within a relatively narrow range

throughout the day (glucose homeostasis). Insulin’s main actions are

(1) In the liver, insulin promotes glycolysis and storage of glucose as glycogen

(glycogenesis), as well as conversion of glucose to triglycerides, (2) In muscle, insulin

promotes the uptake of glucose and its storage as glycogen, and (3) in adipose tissue, insulin

promotes uptake of glucose and its conversion to triglycerides for storage. (El Sayed et al,

2023)

Amylin (diabetes-associated peptide)

Source: Beta cells of islets of the pancreas. It is co-secreted with insulin in response to caloric

intake (feeding state).

Target cells: Alpha cells of islets of pancreas and hypothalamus.

Physiological functions: it suppresses glucagon secretion from the alpha cells of the islets in

the pancreas via paracrine interaction between beta cells and alpha cells. Amylin also slows

10
gastric emptying which delays absorption of glucose from the small intestine into the

circulation. Also, it stimulates the satiety center of the brain to limit food consumption. (El

Sayed et al, 2023)

Glucagon

Source: Alpha cells of islets of the pancreas.

Synthesis: The initial gene product is the mRNA encoding preproglucagon. A peptidase

removes the signal sequence of preproglucagon during translation of the mRNA in the rough

endoplasmic reticulum to yield proglucagon. Proteases in the alpha cells subsequently cleave

the proglucagon into the mature glucagon molecule. (El Sayed et al, 2023)

Target cells: Hepatic cells.

Mechanism of action: glucagon binds to a receptor that activates the heterotrimeric G protein

Gas, which stimulates membrane-bound adenylyl cyclase. The cAMP formed by adenylyl

cyclase, in turn, activates PKA, which phosphorylates numerous regulatory enzymes and

other protein substrates. (El Sayed et al, 2023)

Regulation of its secretion: The amino acids released by digestion of a protein meal appear to

be the main determinant of glucagon secretion.

Physiological functions: Glucagon acts exclusively on the liver to antagonize insulin effects

on hepatocytes. It enhances glycogenolysis and gluconeogenesis. It also promotes oxidation

of fat, which can lead to the formation of ketone bodies. (El Sayed et al, 2023)

Somatostatin

Source: Delta cells of the islets of the pancreas, hypothalamus and D cells of gastric glands.

Target cells: Beta cells of islets of the pancreas, somatotroph cells in the anterior pituitary

gland and the G cells of the gastric glands. (El Sayed et al, 2023)

11
Mechanism of action: Somatostatin binds to a receptor that activates the heterotrimeric

inhibitory G protein, which inhibits membrane-bound adenylyl cyclase and cAMP formation.

Regulation of its secretion: Glucagon stimulates somatostatin secretion via paracrine

interaction between alpha cells and delta cells of the islets of the pancreas. (El Sayed et al,

2023)

Physiological functions: Somatostatin inhibits the secretion of multiple hormones, including

growth hormone, insulin, glucagon, gastrin, vasoactive intestinal peptide (VIP), and thyroid-

stimulating hormone. (El Sayed et al, 2023)

Ghrelin

Source: Epsilon cells of the islets of the pancreas, endocrine cells in the stomach and

hypothalamus.

Target cells: Beta cells of the islets of the pancreas and somatotroph cells in the anterior

pituitary gland.

Physiological functions: Ghrelin inhibits the secretion of insulin from Beta cells of the islets

of the pancreas via paracrine interaction between delta cells and beta cells of the islets of the

pancreas. It also stimulates appetite and growth hormone secretion. (El Sayed et al, 2023)

Pancreatic Polypeptide (PP):

Pancreatic polypeptide is secreted from upsilon (F) cells of the islets of the pancreas. Dietary

intake of nutrients alters the secretion of the pancreatic polypeptide. Its function is not

decidedly understood yet. (El Sayed et al, 2023)

Paracrine Interaction Between Pancreatic Endocrine Cells:

12
Insulin secreted by beta cells acts as a prime hormone of glucose homeostasis. Insulin and

amylin inhibit glucagon secretion by alpha cells. Whereas glucagon activates insulin and

somatostatin secretion, somatostatin secreted by delta cells and ghrelin by epsilon cells

inhibit insulin secretion. (El Sayed et al, 2023)

Clinical Significance:

Diabetes Mellitus (DM) is a chronic disease that occurs when the pancreas cannot produce

enough insulin, or the body cannot effectively utilize insulin, which results in high glucose

plasma level (hyperglycemia) causing tissue damage over time. There are two common types

of DM that account for the majority of cases: type 1 and type 2. (El Sayed et al, 2023)

Type 1 DM

It is a chronic autoimmune disease in which the beta cells of islets of the pancreas are

destroyed resulting in insulin deficiency.

Pathophysiology: It is not entirely understood yet, but it is caused by a combination of events

in genetically susceptible individuals. Three mechanisms lead to islet cell destruction: genetic

susceptibility, autoimmunity, and environmental insult(s). A virus or allergen (environmental

insults) in genetically susceptible individuals induces the production of autoantibodies to

Beta cells of the islets of the pancreas. This autoimmune reaction creates autoreactive T cells

that destroy beta-islet cells and cause loss of insulin secretion. (El Sayed et al, 2023)

Diagnosis: The serum autoantibodies serve as a marker. The autoantibodies are typically

present years before the diagnosis of T1DM is made because clinical manifestations appear

after 80% of beta-islet cells have been destroyed. (El Sayed et al, 2023)

Type 2 DM

13
It is a progressive disease that develops due to a continued decline in beta-cell function

and/or due to a defect in insulin sensitivity that causes hyperglycemia. The development and

rate of progression of T2D are influenced by both genetic and environmental factors, such as

obesity and physical inactivity. (El Sayed et al, 2023)

Pathophysiology: Beta-cell dysfunction manifests in different ways:

1. Reductions in insulin release,

2. Changes in pulsatile insulin secretion,

3. An abnormality in the efficiency of proinsulin to insulin conversion, and

4. Reduces the release of amylin. Insulin resistance is present in most patients with T2D.

Insulin resistance is characterized by higher than expected plasma glucose level with

the prevailing plasma insulin secretion. In patients with T2D insulin, stimulation fails

to induce normal GLUT4 protein translocation to the sarcolemma in skeletal muscle

membrane. Also, excessive production of free fatty acids and overexpression of TNF-

alpha by adipocytes have been proposed as mechanisms for the development of

insulin resistance. (El Sayed et al, 2023)

14
Fig 1: Normal anatomy of pancreas of human being (Patro et al, 2014)

Fig 2: Showing Secondary iron overload inducing chronic panceatitis and ferroptosis of

acinar cells in mice (Chenying Tian et all 2022)

15
Experimental studies of iron overload suggest that iron accumulation in pancreatic islets

impairs insulin secretion and β-cell function and accelerates pancreatic β-cell death (Backe

MB et al, 2016)

IRON AND BETA-CELL DYSFUNCTION

Animal models of the genetic iron-overload disorder hereditary hemochromatosis have

confirmed that iron overload is particularly harmful for the beta cell and have shed light upon

the molecular mechanism of iron overload. In the Hfe knockout mouse (hemochromatosis

model), iron accumulates in the islets, causing increased protein oxidation, decreased insulin

secretion, and increased apoptosis. In addition, rat islets cultured with pharmacologically

relevant concentrations of iron have increased DNA oxidation and decreased viability.

(Backe MB et al. 2016)

Furthermore, patients with transfusional iron overload have increased iron deposition in beta

cells. Ultra-structurally, beta cells of rats treated with ferric nitrilotriacetate have clumped

nuclear chromatin, dilated nuclear membrane, dilated ER, and light secretory granules. Of

note, the observed apoptotic and necrotic features were restricted to beta cells; alpha and

delta cells accumulated iron but did not undergo apoptosis or necrosis.

Iron accumulation in the islet cells of the pancreas, where insulin is produced, can

compromise their function. This impairment leads to an inadequate insulin response to

glucose levels, contributing to insulin resistance and diabetes development. (Backe MB et al.

2016)

GENETICS AND EPIDEMIOLOGY OF IRON OVERLOAD AND DIABETES

The association between diabetes and elevated iron levels was first discovered in patients

with HH by Trousseau in 1865. More than a century later, a prospective study found that

moderate elevations of body iron stores, much lower than those seen in patients with

hemochromatosis, are associated with increased risk of Type 2 Diabetes in a healthy

16
population. Subsequently, several epidemiological studies have confirmed the association

between iron overload and risk of Type 2 Diabetes as well as other insulin-resistant states,

such as metabolic syndrome, polycystic ovary syndrome, and gestational diabetes.

Eventually, the organ damage caused by oxidative stress due to elevated iron levels shortens

survival. (Backe MB et al, 2016)

Metabolic Syndrome, Iron, and Type 2 Diabetes

Although it is well established that an excess of macronutrients, such as fat and

carbohydrates, is involved in the pathogenesis of Type 2 Diabetes, an increasing number of

studies demonstrate that micronutrients, such as iron, are also important factors in the

development of Type 2 diabetes. Accordingly, increased ferritin levels (i.e., increased levels

of body iron stores) are associated with increased risk of Type 2 Diabetes. In patients with

Hereditary Hemochromatosis, circulating levels of ferritin are inversely correlated with

insulin sensitivity. In contrast, lowering the levels of ferritin (e.g., using iron chelators such

as desferoxamine) protects against Type 2 diabetes and phlebotomy improves insulin

sensitivity and glycemic control. Animal studies show that iron deficiency is associated with

increased insulin sensitivity, whereas several human cross-sectional studies support the

correlation between elevated ferritin levels and decreased insulin sensitivity. A large cross-

sectional study reported an association between elevated ferritin levels and the metabolic

syndrome. Furthermore, high levels of ferritin and transferrin were associated with increased

prevalence of the metabolic syndrome in a substudy of the Data from an Epidemiological

Study on the Insulin Resistance. (Backe MB et al, 2016)

2.5.2 COMPLICATIONS OF HEREDITARY HEMOCHROMATOSIS:

Insulin Resistance:

Functionally, iron-overload-mediated diabetes is characterized by both insulin resistance and

insulin deficiency and may therefore mimic both Type 2 Diabetes and idiopathic Type 1

17
Diabetes. Patients with Hereditary Hemochromatosis are more prone to develop diabetes if

insulin resistant because their insulin secretory capacity is decreased, although it is usually

not absent. In the general population, elevated fasting serum ferritin levels are associated with

surrogate measures of both impaired beta-cell function and decreased insulin sensitivity. In

patients with diabetes, it has been shown that iron depletion ameliorates HbA1c levels,

insulin secretion, insulin resistance, and vascular dysfunction. Also, as mentioned above,

phlebotomy may improve insulin secretory capacity and insulin sensitivity if instituted early,

and it reverses impaired glucose tolerance in patients with HH. The pathogenic explanation

for insulin resistance may be hepatic dysfunction due to hepatic iron overload and decreased

skeletal muscle glucose oxidation. (Backe MB et al, 2016)

Oxidative Stress: ¬ Iron-induced oxidative stress in pancreatic tissues exacerbates cellular

damage, influencing the progression of diabetes. Oxidative stress is a key contributor to the

inflammatory milieu observed in individuals with hemochromatosis-associated diabetes.

In conclusion, excess iron adversely affects the pancreas in hemochromatosis, resulting in

disruptions to both endocrine and exocrine functions. The subsequent development of

diabetes mellitus underscores the intricate interplay between iron metabolism and pancreatic

health. Comprehensive understanding of these mechanisms is pivotal for developing targeted

therapeutic interventions and improving outcomes for individuals affected by

hemochromatosis.

2.6 CLINICAL MANIFESTATIONS OF HEREDITARY

HEMOCHROMATOSIS:

The clinical consequences of iron overload tend to be similar regardless of the aetiology and

pathophysiology of the overload. Historically, experts believed that symptoms did not

18
develop until significant organ damage had occurred. However, organ damage is slow and

subtle, and fatigue and nonspecific systemic symptoms and signs often occur early. For

example, liver dysfunction can manifest insidiously with fatigue, right upper quadrant

abdominal pain, and hepatomegaly. Laboratory abnormalities of iron overload and hepatitis

usually precede symptoms. (Hamilton, 2022).

In type 1 hereditary (HFE) hemochromatosis, symptoms relate to the organs with the largest

iron deposits. In men, the initial symptoms may be hypogonadism and erectile dysfunction

caused by gonadal iron deposition. Glucose intolerance or diabetes mellitus is another

common initial presentation. Some patients present with hypothyroidism. (Hamilton, 2022).

Liver disease is the most common complication and may progress to cirrhosis; 20 to 30% of

patients with cirrhosis develop hepatocellular carcinoma. Liver disease is the most common

cause of death. Elevated liver enzymes are one of the most common laboratory abnormalities

in patients with type 1 hemochromatosis. (Hamilton, 2022)

Cardiomyopathy with heart failure is the 2nd most common fatal complication.

Hyperpigmentation (bronze diabetes) and porphyria cutanea tarda are common, as is

symptomatic arthropathy in the hands. (James Peter Adam Hamilton, 2022). (Hamilton,

2022)

In type 2 disease, symptoms and signs include progressive hepatomegaly and

hypogonadotropic hypogonadism. (Hamilton, 2022)

In type 3 disease, symptoms and signs are similar to type 1 hereditary (HFE)

hemochromatosis.

Type 4 disease manifests in the first decade of life as increased serum ferritin levels with low

or normal transferrin saturation; progressive saturation of transferrin occurs when patients are

in their 20s and 30s. Clinical manifestations are milder than in type 1 disease, with modest

liver disease and mild anemia. (Hamilton, 2022)

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2.7 DIAGNOSIS OF HEREDITARY HEMOCHROMATOSIS:

Diagnosis has to rely on clinical features and laboratory tests. Measurements of serum iron,

transferrin saturation and of serum ferritin are the most important non invasive diagnostic

tests. All patients with chronic liver disease should be evaluated for iron overload, regardless

of race or ethnicity

SERUM FERRITIN MEASUREMENT:

Serum ferritin measurement is the simplest and most direct initial test. Elevated levels (> 200

ng/mL [> 200 mcg/L] in women or > 250 ng/mL [> 250 mcg/L] in men) are usually present

in hereditary hemochromatosis but can result from other abnormalities, such as inflammatory

liver disorders (eg, chronic viral hepatitis, nonalcoholic fatty liver disease, alcoholic liver

disease), cancer, certain systemic inflammatory disorders (eg, rheumatoid arthritis,

hemophagocytic lymphohistiocytosis), or obesity. Further testing is done if ferritin level is

abnormal; testing includes fasting serum iron (usually > 300 mg/dL [> 53.7 mmol/L]) and

iron binding capacity (transferrin saturation; levels usually > 50%). A transferrin saturation of

< 45% has a negative predictive value of 97% for iron overload. (Hamilton, 2022)

In type 2 disease, ferritin levels are >1000 ng/mL (> 1000 mcg/L), and transferrin saturation

is >90%.In transferrin or ceruloplasmin deficiency, serum transferrin (ie, iron-binding

capacity) and ceruloplasmin levels are profoundly low or undetectable. (Hamilton, 2022)

GENE ASSAY

Gene assay is diagnostic of hereditary hemochromatosis caused by HFE(High Iron Fe) gene

mutations. About 70% of patients with C282Y homozygous mutations of the HFE gene have

an elevated ferritin level, but only about 10% of these patients have evidence of organ

dysfunction. Clinically significant iron overload is even less common in patients with

heterozygous mutations of the HFE gene (ie, C282Y/H63D). Hemochromatosis types 2 to 4

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are suspected in the less common instances in which ferritin and iron blood tests indicate iron

overload and genetic testing is negative for the HFE gene mutation, particularly in younger

patients. Confirmation of these diagnoses by genetic testing is not routinely available.

(Hamilton, 2022)

LIVER BIOPSY

When the diagnosis is confirmed, the liver must be tested for fibrosis and cirrhosis. Up to

80% of patients with cirrhosis and a homozygous C282Y mutation will have a ferritin of >

1000 ng/mL, elevated AST (aspartate transaminase) and ALT (alanine transaminase), and

platelet count < 200 × 103 /mcL (< 200 × 109/L). Because the presence of cirrhosis affects

prognosis, when the ferritin is > 1000 ng/mL, liver biopsy is commonly done and tissue iron

content is measured (when available). Liver biopsy is also recommended in patients with

serologic evidence of iron overload but negative genetic evaluation. MRI with noncontrast

MR elastography (MRE), a noninvasive alternative for estimating hepatic iron content and

hepatic fibrosis, is becoming increasingly accurate. (Hamilton, 2022)

Screening is required for first-degree relatives of people with hereditary hemochromatosis by

measuring serum ferritin levels and testing for the C282Y and H63D mutations in the HFE

gene. (Hamilton, 2022)

Iron-Binding Capacity (IBC): Iron binding capacity is the capacity of transferrin to bind

with iron. Iron binding capacity is of two types, TIBC and unsaturated iron-binding capacity

(UIBC). When iron stores are depleted, the transferrin levels increase in the blood. As only

one-third of transferrin is saturated with iron, so the transferrin present in serum has an extra

binding capacity (67%). This is unsaturated iron-binding capacity. TIBC is the total of serum

iron and UIBC. TIBC is used in both iron deficient and overload scenarios to establish the

diagnosis. In iron overloaded states of the body; the quantity of free transferrin in blood

decreases, and consequently, TIBC values are low. (Faruqi A, 2023)

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Hemoglobin and Hematocrit: - Hemoglobin and hematocrit levels indicate the amount of

iron available for red blood cell production (Assi and Baz, 2014). Iron overload can lead to

anemia, but paradoxically, some individuals with iron overload may have normal or elevated

hemoglobin, levels (Tavill and Adams 2016).

2.8 TREATMENT OF HEREDITARY HEMOCHROMATOSIS

Treatment is indicated for patients with clinical manifestations, elevated serum ferritin levels

(particularly levels > 1000 ng/mL [> 1000 mcg/L]), or elevated transferrin saturation.

Asymptomatic patients need only periodic (eg, yearly) clinical evaluation and measurement

of serum iron, ferritin, transferrin saturation, and liver enzymes . (James Peter Adam

Hamilton, 2022)

2.8.1 PHLEBOTOMY:

Phlebotomy is the simplest and most effective method to remove excess iron. It delays

progression of fibrosis to cirrhosis, sometimes even reversing cirrhotic changes, and prolongs

survival, but it does not prevent hepatocellular carcinoma. About 500 mL of blood (about 250

mg of iron) is removed weekly or biweekly (every other week) until serum ferritin levels

reach 50 to 100 ng/mL. Weekly or biweekly phlebotomy may be needed for many months

(e.g., if 250 mg of iron are removed per week, 40 weeks will be required to remove 10 g of

iron). When iron levels are normal, phlebotomies can be intermittent to maintain ferritin

between 50 and 100 ng/mL. (Hamilton, 2022)

Diabetes mellitus, cardiomyopathy, erectile dysfunction, and other secondary manifestations

are treated as indicated. Patients with advanced fibrosis or cirrhosis due to iron overload

should be screened for hepatocellular carcinoma every 6 months with a liver ultrasound.

(Hamilton, 2022)

2.8.2 DIET AND MEDICATIONS

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Patients should follow a balanced diet; it is not necessary to restrict consumption of iron-

containing foods (e.g., red meat, liver). Alcohol should be consumed only in moderation

because it can increase iron absorption and, in high amounts, increases the risk of cirrhosis.

Vitamin C supplements should be avoided because they increase the absorption of iron in the

duodenum (Hamilton, 2022)

In patients with type 4 disease, tolerance to vigorous phlebotomy is poor; serial monitoring of

haemoglobin level and transferrin saturation is required. Treatment of transferrin deficiency

and ceruloplasmin deficiency is experimental; e.g. iron chelators may be better tolerated than

phlebotomy because patients typically have anaemia. (Hamilton, 2022)

23
 CONCLUSION

In conclusion, this exploration into hemochromatosis and its impact on pancreatic health

underscores the intricate relationship between iron overload and organ dysfunction. The

evidence presented highlights the potential consequences of excessive iron accumulation in

the pancreas, emphasizing the need for a comprehensive understanding of hemochromatosis

beyond its classical effects on the liver and heart. As we delve deeper into the molecular

mechanisms linking hemochromatosis and pancreatic health, there emerges a clearer picture

of the intricate pathways that may contribute to diabetes and other pancreatic disorders in

individuals with iron overload. Recognizing these connections is pivotal for early detection,

intervention, and the development of targeted therapies to mitigate the pancreatic

complications associated with hemochromatosis. Continued research in this field holds

promise for advancing our knowledge and improving the management of individuals affected

by this hereditary iron disorder.

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 RECOMMENDATION

Screening Programs: Implementing routine screening programs for hemochromatosis,

especially in populations with a higher prevalence of this genetic disorder, to enable early

detection and intervention.

Interdisciplinary Approach: Encouraging a collaborative approach among healthcare

professionals, including hematologists, endocrinologists, and gastroenterologists, to

comprehensively manage individuals with hemochromatosis and monitor pancreatic health.

Patient Education: Providing thorough education to individuals diagnosed with

hemochromatosis about the potential impact on pancreatic health, emphasizing the

importance of regular check-ups and adherence to treatment protocols.

Research Investment: Allocating resources for further research into the specific molecular

pathways connecting hemochromatosis and pancreatic dysfunction, aiming to uncover novel

therapeutic targets and treatment strategies.

Genetic Counseling: Offering genetic counseling for individuals with a family history of

hemochromatosis to assess the risk and facilitate informed decision-making regarding

screening and preventive measures.

Policy Considerations: Advocating for policies that support the inclusion of

hemochromatosis in public health initiatives, ensuring awareness, early detection, and

appropriate management.

By incorporating these recommendations, there is potential for enhancing the overall care and

outcomes for individuals affected by hemochromatosis, with a particular focus on preserving

pancreatic health and preventing associated complications.

25
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