Overview

Definition

Hereditary hemochromatosis (HH) is:

• The most common autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder in Caucasians
• The most frequent cause of severe iron overload
• Caused by different gene mutations that ultimately lead to low production of hepcidin, resulting in increased iron absorption

Etiology

• HFE gene: 
  • Specific for HH
  • Within the human leukocyte antigen (HLA) region on chromosome 6
  • Common missense mutations in the HFE gene: 
    • C282Y (cysteine-to-tyrosine substitution at amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids position 282)
    • H63D (histidine-to-aspartic acid substitution at amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids position 63)
  • Common HH genotypes:
    • Homozygosity for C282Y (C282Y/C282Y)
    • Compound heterozygosity (C282Y/H63D) 
• Non-HFE gene:
  • Mutations in other genes involved in iron metabolism
  • Rare 
  • Found in juvenile hemochromatosis
• Effects of gene mutations:
  • ↑ Iron absorption in the intestine: up to 2–4 mg of dietary iron/day (normal: 1–2 mg/day)
  • ↑ Iron deposition in different organs (e.g., liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver)

Iron overload

It is important to note that causes of iron overload may overlap or occur at the same time.

Secondary iron overload disorders (acquired):

• Common causes:
  • Increased iron intake (transfusions) 
  • Ineffective erythropoiesis Erythropoiesis Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. Erythrocytes ( thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia)
  • Loss of hepatocyte mass resulting in reduced hepcidin (chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease) 
• Iron deposits affecting different organs exhibit similar clinical and pathologic features as HH.

Epidemiology

• 1 in 200–500 people
• Highest in people of Celtic or Nordic origin
• C282Y variant: 
  • Most common finding in patients with HH
  • 85% of patients with HH are homozygous for the C282Y mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations.
• Less common in people of African descent
• Men affected 2–3 times more than women
• Age of onset:
  • Men: after 40 years
  • Women: after 50 years
  • Juvenile hemochromatosis: onset at age 10–30 years
• Mortality: 1.7 cases per 10,000 deaths

Pathophysiology

Iron homeostasis

1. Dietary iron undergoes intestinal uptake in the duodenum.
2. Iron moves from the duodenum via the iron exporter, ferroportin (Fpn), and enters the circulation via transferrin (Tf).
3. Transferrin supplies iron to the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow for hemoglobin synthesis.
4. As the red blood cells (RBCs) age, they are phagocytosed by macrophages (in the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen), releasing iron again into the circulation through Fpn. 
5. Iron that is not used for biochemical processes is stored in ferritin.

Iron regulation via hepcidin

Certain conditions require a decrease or increase in iron absorption and circulating iron, a pathway regulated by hepcidin:

• Liver-derived peptide regulating the plasma iron concentration
• Actions (through binding Fpn):
  • Inhibits intestinal iron uptake
  • Inhibits the release of iron from macrophages with old RBCs
• Iron sensing is mediated by different proteins: 
  • HFE
  • Transferrin (Tf) receptor 2 (Tfr2)
  • Hemojuvelin
• Affected by:
  • ↑ Iron: ↑ hepcidin to reduce iron
  • ↑ Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation: ↑ hepcidin to limit iron availability to microorganisms
  • ↑ Erythropoietin: ↓ hepcidin to increase iron for hematopoiesis

Mutations in the hepcidin pathway

• HH:
  • Gene mutations involving the HFE protein and non-HFE proteins (Tfr2, hemojuvelin, Fpn, and hepcidin) → decreased hepcidin release and increased iron absorption
  • Increased iron absorption → saturation of Tf and progressive increase of ferritin → iron overload → iron deposition
• ↑ iron results in excess oxidative stress → inflammation and cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death → organ damage

Types of HH

• Type 1 (HFE related): classic form of HH 
• Type 2: juvenile hemochromatosis:
  • Type 2a: mutations of the hemojuvelin gene 
  • Type 2b: mutations of the hepcidin gene 
• Type 3: mutations of the Tf receptor-2 gene  
• Type 4: mutations of the Fpn gene

Clinical Presentation

General findings

• Manifestations depend on the degree of iron accumulation.
• Often asymptomatic; diagnosed incidentally on blood tests or on family screening
• Liver: 1st organ to be affected
• Classic triad (found late in the disease):
  1. Cirrhosis
  2. Diabetes (“bronze diabetes” due to the associated discoloration)
  3. Skin bronzing/increased pigmentation

Specific findings and complications

• Liver:
  • Abnormal liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests
  • Hepatomegaly (in 95% of patients), abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease/ cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis: palmar erythema, spider angiomas, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
  • Hepatic failure: encephalopathy, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
• Pancreas: 
  • Diabetes: elevated glucose
  • Fatigue, polyuria, polydipsia, weight loss, recurrent infections
• Skin:
  • Bronze/slate-grey skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin coloration (melanoderma)
  • Prominent on face, neck, forearms, and genital regions
  • Koilonychia (spoon-shaped nails)
• Heart:
  • Dilated cardiomyopathy Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is the most common type of non-ischemic cardiomyopathy and a common cause of heart failure (HF). The cause may be idiopathic, familial, or secondary to a variety of underlying conditions. The disease is characterized by the enlargement of 1 or both ventricles and reduced systolic function. Dilated Cardiomyopathy, congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
  • Arrhythmias
• Joints:
  • Arthralgia: small joints of the hands, especially the 1st, 2nd, and 3rd metacarpophalangeal joints
  • Others: knees, wrists
  • No joint warmth, redness, or deformity
  • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
• Pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland:
  • Hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism (most common pituitary dysfunction): infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility, loss of libido, amenorrhea
  • Adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease
  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
  • Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism
• Decreased host defenses: 
  • Impaired phagocytosis and reduced lymphocyte proliferation, with readily available iron to microorganisms
  • ↑ Risk of infection from Listeria Listeria Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria Monocytogenes Infections monocytogenes, Yersinia Yersinia Yersinia is a genus of bacteria characterized as gram-negative bacilli that are facultative anaerobic with bipolar staining. There are 2 enteropathogenic species that cause yersiniosis, Y. enterocolitica and Y. pseudotuberculosis. Infections are manifested as pseudoappendicitis or mesenteric lymphadenitis, and enterocolitis. Enterobacteriaceae: Yersinia spp./Yersiniosis enterocolitica, and Vibrio Vibrio Vibrio is a genus of comma-shaped, gram-negative bacilli. It is halophilic, acid labile, and commonly isolated on thiosulfate-citrate-bile-sucrose (TCBS) agar. There are 3 clinically relevant species: Vibrio cholerae (V. cholerae), Vibrio vulnificus (V. vulnificus), and Vibrio parahaemolyticus (V. parahaemolyticus). Vibrio vulnificus

Diagnosis

Laboratory tests

• Tf saturation (TSAT): ratio of serum iron to total iron-binding capacity (TIBC): 
  • If > 45% → screen for hemochromatosis
  • If > 60% (men) and > 50% (women) → highly specific for diagnosis
• Serum iron: > 150 mcg/dL
• TIBC: 200–300 mcg/dL
• Serum ferritin: 
  • An acute phase reactant
  • Less sensitive, because serum ferritin can be ↑ in other liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and inflammatory diseases
  • Indicative of disease when: 
    • > 200 mcg/L in premenopausal women
    • > 300 mcg/L in men and in postmenopausal women
    • If > 1,000 mcg/L → increased risk of organ damage
• Abnormal liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests: ↑ alanine transaminase (ALT), ↑ aspartate transaminase (AST)
• Additional tests: 
  • Hormone tests in cases consistent with pituitary disorders
  • Hemoglobin A1c and metabolic panel in those with diabetes

Genetic testing

• C282Y and H63D mutations in the HFE gene
• Homozygous for C282Y or heterozygous for C282Y/H63D: indicative of HH
• Screen all 1st-degree relatives.

Imaging

• Radiographs: may see cardiomegaly and pulmonary vascularity
• Magnetic resonance imaging (MRI) of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: 
  • Evaluates liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver damage or tumor development
  • Noninvasive way to estimate iron stores
• Cardiac MRI: performed for those with cardiac failure
• Echocardiogram: shows dilated cardiomyopathy, diastolic dysfunction

Biopsy

• Skin: can sample any site except for legs (may be non-specific due to stasis)
• Liver biopsy: 
  • Performed when initial approach yields uncertain results
  • Indications:
    • Abnormal liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests
    • Ferritin > 1,000 mcg/L
    • Other liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease is suspected.
  • Helps determine the extent of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver damage and iron concentration
  • Hepatic fibrosis: most important prognostic factor

Management and Prognosis

Management

• Objectives:
  • Remove excess iron from the body.
  • Reduce progression of disease and complications, including risk for HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases.
• Phlebotomy:
  • Treatment of choice
  • Performed weekly or twice weekly, removing 500 mL, and continued until the serum ferritin level is approximately 50–100 mcg/L
  • After ferritin drops to the goal level, it is maintained with phlebotomy (the frequency depends on serum iron studies and blood count). 
  • Can improve or slow the natural disease progression
• Iron chelating agents:
  • Treatment options for patients who have heart disease, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, or difficult intravenous access
  • Options:
    • Deferoxamine: intravenous/intramuscular/subcutaneous
    • Deferiprone: oral chelator (↓ cardiac iron overload)
    • Deferasirox: oral iron chelator
• Dietary restrictions:
  • No iron supplements
  • Limit vitamin C supplements (↑ iron absorption).
  • No alcohol to limit liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver injury
  • No raw seafood ( Vibrio Vibrio Vibrio is a genus of comma-shaped, gram-negative bacilli. It is halophilic, acid labile, and commonly isolated on thiosulfate-citrate-bile-sucrose (TCBS) agar. There are 3 clinically relevant species: Vibrio cholerae (V. cholerae), Vibrio vulnificus (V. vulnificus), and Vibrio parahaemolyticus (V. parahaemolyticus). Vibrio vulnificus contamination → sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock) 
• Complication-specific treatments:
  • Conventional therapy for diabetes, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, and cardiac failure/arrhythmia 
  • Hormone replacement or gonadotropin therapy for pituitary effects
  • HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases screening for those at high risk
• Surgical management for advanced complications:
  • Liver transplantation: for liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure
  • Arthroplasty: for severe joint infiltration

Prognosis

• With treatment:
  • 5-year survival rate: 89%
  • Patients without hepatic fibrosis: expected to have a normal life expectancy
• Effects of treatment/phlebotomy on complications:
  • Cardiac failure may be reversed.
  • Liver function and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin pigmentation improve.
  • 40% of patients with diabetes reach better glucose control.
  • Minimal effect on arthropathy and hypogonadism
• Once liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis sets in, it is irreversible; HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases is a late sequela.
• Main causes of death:
  • Cardiac failure
  • Hepatic failure
  • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases

Differential Diagnosis

• Alcoholic liver disease Alcoholic Liver Disease Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice, fever, and abdominal pain. Alcoholic Liver Disease: Patients with a history of chronic alcoholism and who have developed chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease and cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis may manifest with increased iron levels. Treatment is alcohol cessation.
• Multiple transfusions: In patients who require a lot of blood transfusions (patients with thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia, myelodysplastic syndrome), there may be an increased iron level, comparable to patients with hemochromatosis. Levels return to normal after transfusions are stopped. 
• Chronic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview: a condition of chronically low RBC counts. Due to the body adjusting to chronic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, there is increased efficient erythropoiesis Erythropoiesis Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. Erythrocytes and iron absorption. Treatment is iron replacement in addition to treating the underlying cause.