What are stimulators of HCL secretion?
Histamine
Acetylcholine
Gastrin (G cells)
(HAG)
What are the inhibitors of HCL secretion?
Somatostatin (D cells)
Secretin (S cells)
GIP (K cells)
Cholecystokinin (I cells)
(SSGC)
What does the duodenum, jejunum, ileum absorb?
Duodenum - iron
Jejunum - folate
Ileum - b12 which needs to bind to intrinsic factor, bile salts
Dude Is Just Feeling Ill, Bro
What is the pathophysiology of pernicious anaemia?
Autoimmune destruction of parietal cells → ↓ intrinsic factor production → ↓ absorption of B12 in the terminal ileum → pernicious anemia
What does elevated gastrin levels indicate?
Elevated serum gastrin levels can be used to support the diagnoses of atrophic gastritis and Zollinger-Ellison syndrome.
What is ghrelin involved in and what conditions if its levels are high or low
Ghrelin - hunger!
- Ghrelin is increased in Prader-Willi syndrome
- Ghrelin is decreased following gastric bypass surgery.
Prader Willi Syndrome: genetic syndrome caused by microdeletion of the paternal gene copy at 15q11-a13. Characterised by muscular hypotonia during infancy, genital hypoplasia, short stature and hyperphagia, which often results in morbid obesity.
What is the pathophysiology of achalasia?
In achalasia, degeneration of inhibitory neurons within the myenteric plexuses (Auerbach plexus) → deficient inhibitory neurotransmitters such as nitric oxide and vasoactive intestinal peptide → higher resting pressures of the lower esophageal sphincter
Anatomy of Oesophagus
• Outer longitudinal muscle layer and inner circular muscle layer
• Auerbach’s myenteric plexus in between muscle layers
• Meissner’s submucosal plexus beneath circular muscle layer
• Top 1/3 is striated muscle; lower 2/3 is smooth muscle
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Where is iron absorbed?
In the duodenum and upper jejunum
What is hepcidin?
- Hepcidin is an enzyme that regulates the intestinal absorption of iron
- Hepcidin is produced in response to INCREASED levels of plasma iron, INFLAMMATION or the HFE protein and act to inhibit iron uptake into the circulation
- Hepcidin is synthesised in the LIVER
- It INHIBITS ferroportin and decrease absorption of iron
- Its production is regulated by the human haemochromatosis protein (HFE protein)
- Increased body stores of iron → ↑ HFE protein → ↑ hepcidin → prevention of iron absorption
- Iron deficiency → ↓ hepcidin → ↑ iron absorption
What increases the absorption of iron?
What decreases the absorption of iron?
- Vitamin C increases absorption of iron (converts Fe3+ to Fe2+)
- Calcium and zinc decreases absorption of iron (due to chelation of iron)
Where is iron stored?
Stored mainly in the liver as ferritin and hemosiderin
How is iron transported?
- The enzyme CERULOPLASMIN oxidises ferrrous iron back to ferric iron (converts Fe 2+ to Fe 3+)
- Transferrin binds and transports the ferric iron Fe3+ to the erythroid precursor cells (in the bone marrow) for haemoglobin synthesis
What enzyme causes dietary iron to be released from ingested food?
Dietary iron is released from ingested food in the stomach by the action of GASTRIC ACID and PEPSIN.
Gastric acid converts the ferrous form (Fe2+) to the ferric (Fe3+) form.
Iron absorption and circulation
Intake: Dietary source; Haem iron (Ferrous, Fe2+) and non Haem iron (Ferric, Fe3+)
Absorption: Duodenum and jejunum
-Vit C Ferric reductase duodenal cytochrome B expressed on the apical border of intestinal cells reduce Fe3+ to Fe2+
•Enhanced by Vitamin C
•Suppressed by Calcium and zinc
-Fe2+ is absorbed via surface transporter into the enterocyte, DMT1 (LUMINAL)
-Fe2+ is bound to apoferritin and stored as ferritin
-Fe2+ is oxidised to Fe3+ by feroxidase(Hephastin) and ferroportin transports Fe3+ across the basolateral membrane (FERROPORTIN - BASOLATERAL)
•Hepcidin produced by the liver binds to ferroportin and causes its internalisation and degradation
•Hepcidin synthesis is upregulated by high levels of iron in the liver the BMP signaling pathway
•Hepcidin release is upregulated by IL6, Fe3-Transferrin complexes, HFE protein encoded by HFE gene, and low vitamin D
Circulation
- Fe3+ binds to transferrin, which is produced in the liver
- This complex prevents toxic effects of iron and also allows iron to be taken up by cells that express transferrin receptors (GPCR) , and apoferritin is released thereafter to be reused
- Transferrin Receptor 1: high affinity, found in all cells
- Transferrin Receptor 2: low affinity, found in hepatocytes
What is haemochromatosis and what are the 2 main types?
- Condition that leads to abnormal iron deposition in specific organs.
2 main types
- Primary (hereditary)
- Secondary (transfusion related)
The most common form is hereditary autosomal recessive hemochromatosis type 1, which is caused by an underlying genetic defect that results in partially uninhibited absorption of iron in the small intestine
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Cause of haemochromatosis
(A) PRIMARY (HEREDITARY)
HAEMOCHROMATOSIS
- Classical and most frequent form: adult hemochromatosis type I
- Inheritance: autosomal recessive with incomplete penetrance
- Needs 2 mutations: C282Y, H63D
- Homozygous or heterozygous for the HFE gene defect
- Located on chromosome 6
Most commonly affects C282Y and H63D
- Associated with HLA-A3 genotype - “HLA A3 as in HA3mochromatosis”
(B) SECONDARY HEMOCHROMATOSIS
- Caused by iron overload
Transfusion-related (e.g., in individuals with β-thalassemia major or other forms of chronic anemia requiring chronic transfusion)
- Ineffective erythropoiesis secondary to:
(a) Thalassemia
(b) Sickle-cell anemia
(c) Sideroblastic anemia (e.g.,hereditary sideroblastic anemia; anemia of chronic disease
- Excessive alcohol consumption
Pathophysiology of hemochromatosis type 1?
- The HFE gene regulates iron homeostasis
- HFE gene defect (homozygous) → defective binding of transferrin to its receptor → ↓ hepcidin synthesis by the liver → unregulated ferroportin activity in enterocytes → ↑ intestinal iron absorption → iron accumulation throughout the body → damage to the affected organs
- In hereditary hemochromatosis, decreased hepcidin leads to iron overload.
- In secondary hemochromatosis, iron overload leads to increased hepcidin immediately after a blood transfusion (unless liver fibrosis or cirrhosis , which leads to decreased hepcidin synthesis, is present).
Clinical features of hemochromatosis
- Asymptomatic in 75% of cases
- General symptoms: fatigue, lethargy, increased susceptibility to infections
- Hyperpigmentation
- DM - bronze diabetes (diabetes + bronze skin)
- Arthralgia
Organ specific
- Liver: cirrhosis, hepatomegaly, abdominal pain, increased risk of HCC
- Pancreas: diabetes
- Skin; hyperpigmentation, bronze skin
- Heart: cardiomyopathy, arrythmias
- Joints: arthralgia, typically symmetrical arthropathy of the MCP joints II and III
Investigations for hemochromatosis
Elevated iron Elevated ferritin Elevated transferrin Elevated liver enzymes Low total iron binding capacity
HFE gene mutations
- Homozygous C282Y
- Homozygous H63D
- Heterozygous C282Y/H63D
MRI: iron concentration in liver
CXR + TTE: cardiac hemochromatosis
Liver Biopsy:
- Indications: elevated liver enzymes caused by hereditary hemochromatosis; increased serum ferritin levels (> 1000 μg/L)
- Histology
Color stain: Prussian blue
Pronounced siderosis in iron staining with iron deposits primarily observed in hepatocytes
Macrophages containing hemosiderin: cytoplasmic granules that stain golden-yellow (caused by chronic hemolysis)
Cirrhosis is unusual if ferritin < 1000
Standard practice is to maintain between 50-100
Treatment of hemochromatosis
PRIMARY HEMOCHROMATOSIS
Dietary Changes
- Low iron diet
- Restriction of alcohol + vitamin C supplements
Therapeutic Phlebotomy (1st line treatment) Indications: Ferritin >1000, evidence of tissue injury (eg: increased hepatic transaminases, reduced EF), increased tissue iron by MRI/biopsy
Drug induced chelation
- Used when phlebotomy is contraindicated, eg: in cases of anaemia, severe heart disease, difficult venipuncture
- Agents: deferoxamine, deferasirox or deferiprone
- Indication: particularly when phlebotomyis contraindicated, e.g., in cases of anemia, severe heart disease, or difficult venipuncture
Drugs that delete iron (Fe) in hemochromatosis: deFeroxamine, deFerasirox, deFeriprone.
SECONDARY HEMOCHROMATOSIS
- Depends on underlying cause
- Consider iron chelating therapy
- Phlebotomy not advisable
If the risk of progression is suspected to be low (eg, due to a negative family history, ferritin <500 ng/mL, transferrin saturation [TSAT] <60 percent, and normal liver function tests), patients can be monitored annually with repeat iron studies, reserving phlebotomy for those who have a progressively increasing ferritin level, TSAT, and/or evidence of disease progression
Which of the following is the primary mechanism of body iron regulation?
A. Shedding of duodenal enterocytes.
B. Regulation of enterocyte surface expression of transferrin receptor (TfR1).
C. Regulation of enterocyte ferritin content.
D. Renal haemosiderin excretion.
E. Alteration of Kuppfer cell iron metabolism gene expression.
A. Shedding of duodenal enterocytes.
What is plummer vinson syndrome associated with?
- IDA can be associated with Plummer-Vinson syndrome
- Triad of iron deficiency anemia, postcricoid dysphagia, and upper esophageal webs
- Associated with an increased risk of esophageal squamous cell carcinoma and glossitis
- Etiopathogenesis unknown
DICEd Plumm - Dysphagia, Iron deficiency anemia, Carcinoma of the esophagus, Esophageal webs in Plummer-Vinson syndrome.
Causes of jaundice
(A) Prehepatic
Haemolysis: G6PD deficiency, spherocytosis
Ineffective Erythropoiesis: thalassemia, pernicious anaemia (vit b12 deficiency)
High UNCONJUGATED BILIRUBIN
Dar stool, normal urine
(B) Intrahepatic
- Non obstructive biliary disease - hepatitis, liver cirrhosis, primary biliary cirrhosis
- Mechanical biliary obstruction: tumours of the liver, intrahepatic gallstones, primary sclerosing cholangitis
(C) Posthepatic
- Choledocholithasis
- Tumours
- Bile duct strictures
Intrahepatic + Post hepatic - high conjugated bilirubin, pale stools, dark urine
Bilirubin metabolism
- Bilirubin is a normal breakdown production from the catabolism of haem
- Bilirubin undergoes conjugation within the liver making it water-soluble
• In the bloodstream, unconjugated bilirubin binds to albumin to facilitate its transport to the liver. Once in the liver, glucuronic acid is added to unconjugated bilirubin by the enzyme glucuronyl transferase. This forms conjugated bilirubin, which is soluble. This allows conjugated bilirubin to be excreted into the duodenum in bile. - Excreted via the bile into the GI tract and the majority is egested in the faeces as urobilinogen and stercobilini
Bilirubin Excretion
• Once in the colon, colonic bacteria deconjugate bilirubin and convert it into urobilinogen. Around 80% of this urobilinogen is further oxidised by intestinal bacteria and converted to stercobilin and then excreted through faeces. It is stercobilin which gives faeces their colour.
• Around 20% of the urobilinogen is reabsorbed into the bloodstream as part of the enterohepatic circulation. It is carried to the liver where some is recycled for bile production, while a small percentage reaches the kidneys. Here, it is oxidised further into urobilin and then excreted into the urine.
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