This powerpoint presentation is about hereditary hemochromatosis

1. HEREDITARY
HEMOCHROMATOSIS
Dr. Ali Khurshid Bhalli
PGR Gastroenterology

2. Case Scenario
A 52-year-old male presented with impotence. He had a four-year history
of insulin-dependent diabetes mellitus. There was no history of headaches
or vomiting. The patient was a non-smoker and did not consume alcohol.
Apart from insulin he took simple analgesia for joint pains.
Investigations are shown

3. Investigations
• Thyroxine 100 nmol/l
• TSH 2.6 mu/l
• Testosterone 7 nmol/l (NR 10–35 nmol/l)
• LH 1.5 iu/l (NR 1–10 iu/l)
• FSH 1 iu/l NR 1–7 iu/l)
• LHRH test: 20 min: 60 min:
• LH 3 iu/l 2 iu/l
• FSH 2 iu/l 2 iu/l
FBC Normal
Sodium 135 mmol/l
Potassium 4 mmol/l
Urea 6 mmol/l
Creatinine 100 mmol/l
Bilirubin 12 mmol/l
AST 200 iu/l
ALT 220 iu/l
Alkaline phosphatase 128 iu/l
Albumin 8 g/l
Serum Ferritin 2573 (22-322 ng/ml)
TIBC 217 (250-450 ug/dl)
Transferrin Saturation 83 % (15-50%)

4. • An abdominal ultrasound showed an enlarged liver with a nodular
surface. No intrahepatic biliary dilatation. There were small choleliths in the
gallbladder without obstruction.

5. Liver Biopsy
• A liver biopsy findings are shown as:

6. Low power shows minimal nonspecific
mononuclear inflammation predominantly in
the periportal area. There is mild fibrosis on
H&E stain. There are numerous golden-
brown fine pigment depositions in
hepatocytes.

7. Higher magnification shows the fine golden-
brown pigment accumulation within
hepatocytes.

8. Iron stain again shows a marked periportal
iron deposition (Arrowhead) with decreased
gradient to the centrilobular area (Arrow)

9. Diagnosis
• Heridetary Hemochromatosis ( with insulin dependent diabetes, arthropathy
and secondary hypogonadism)

10. Introduction
• “Celtic Curse” also known as “ Bronze diabetes”
• Genetic haemochromatosis is one of the most frequent genetic disorders
found in Northern Europeans.
• Abnormal accumulation of iron in parenchymal organs such as liver,
pancreas, heart and joints causes widespread tissue damage including diabetes
mellitus & cirrhosis.

11. History
• Classic triad (cirrhosis, diabetes and skin pigmentation) described in 1865 by
Trousseau.
• Named “Haemochromatosis” in 1889 by Von Reckhinghaussen.
• Inheritence described in 1935
• HLA linkage to chromosome 6 identified 1976

12. Epidemiology
• Hereditary haemochromatosis remains the most common genetic disorder in
Caucasian.
• Female : male – 1: 10
• Population screening has shown prevalence of heterozygous is about 10%
• C282Y homozygous account for 80 - 85%

13. • HFE gene mutation- identified 1996
• Autosomal recessive
• C282Y or H63D
• Cysteine tyrosine at 282 (C282Y)
• Histidine aspartate at 63 (H63D)

14. The HFE Gene
• HFE gene on chromosome 6
- involves in iron homeostasis
• Two common mutations on HFE
- C282Y allele : over 90% patients
- H63D allele
• HFE gene mutations produces altered HFE protein unable to properly
regulate iron metabolism results in excess of iron storage.

15. Iron Balance
• Total body iron is 4 gm :
Haemoglobin – 3 gm
Myoglobin - 300 mg
Enzymes & cytochromes – 100 mg
Transferrin - 4 mg
• Daily loss : 1mg (due to desquamation of cells)
In females : 15-40 mg/menstruation
500 mg/pregnancy

16. Types of Hereditary Hemochromatosis
• Type 1 (HFE related) – Most common, adult-onset, 40-60 years. C282Y and
H63D are the most common mutations of the HFE gene on chromosome 6.
• Type 2a (mutation of hemojuvelin gene, HJV), Type 2b (mutation of HAMP
gene) – Early onset, 15-20 years.
• Type 3 (mutation of transferrin receptor- gene, TfR2) – Onset at 30-40 years.
• Type 4 (mutation of ferroportin gene) – Autosomal dominant, onset at 10-80
years, limited clinical consequences.

17. Pathophysiology
•HFE mutation → ↓ hepcidin production
•Low hepcidin → Ferroportin stays active
•Results in:
•↑ intestinal iron absorption (mainly in duodenum)
•↑ iron release from macrophages and hepatocytes
•This leads to iron overload in plasma and tissues

18. • Iron overload → generates reactive oxygen species (ROS)
• ROS cause oxidative damage to DNA, lipids, and proteins
• Iron deposits primarily in:
• Liver → fibrosis, cirrhosis, hepatocellular carcinoma
• Pancreas → diabetes mellitus
• Joints → arthropathy (esp. 2nd/3rd MCP joints)
• Heart → cardiomyopathy
• Endocrine organs → hypogonadism

20. Clinical Presentation
• Liver function abnormalities – 75%
• Weakness and lethargy – 74%
• Skin hyperpigmentation – 70%
• Diabetes mellitus – 48%
• Arthralgia – 44%
• Impotence in males – 45%
• ECG abnormalities – 31%

21. Diagnosis
• Transferrin saturation : >45% indicate significant iron accumulation in women
and >50 % in men
• Plasma ferritin : normal 40 to 200 ng/ml
> 200 mcg/L in premenopausal women
> 300 mcg/L in men and postmenopausal women
• Liver biopsy – if ferritin > 1000 mcg/L
• Consider genetic testing – DNA testing for common mutation (C282Y, H63D)

22. Liver Biopsy
Liver biopsy should be considered :
• For the purpose of determining the presence or absence of advanced
fibrosis or cirrhosis.
• Screening of HCC.
• For measurement of HII.( 1.9 or more is suggestive of HH)

23. Genetic Testing
Should be offered to those patients with-
• Appropriate clinical presentation.
• Elevated transferrin saturation and ferritin.
• Liver biopsy suggestive of iron overload.
• First degree relative of known case.

24. Differential Diagnosis
• Hepatomegaly: fatty liver
• Diabetes: Cushing syndrome
• Cardiac: amyloidosis, sarcoidosis
• Arthritis: RA, pseudogout
• Hyperpigmentation: hyperbilirubinemia
• Cirrhosis from other causes

25. Management
• General Management
• Avoid alcohol consumption
• Screening for hepatitis b and hepatitis c
• Vaccination against hepatitis a and b
• Avoid iron containing diet, vitamin C, raw shellfish and supplemental iron.

26. Phlebotomy: initiation phase
Venesection is indicated for all fit patients with biochemical iron overload with
or without clinical features.
• Initially once weekly (450-500 ml, ~200-250 mg iron)
• Monitor Hb levels weekly, SF monthly, Tsat 1-3 monthly and reduce rate of
venesection if anaemia develops.
• Continue for upto2 to 3 years for depletion of iron stores
• Continue until SF is 20-30 mcg/L and Tsat is <50%

27. Maintenance Phase
• Once excess iron removed and venesection ceased, iron will begin to re-
accumulate.
• Patients usually come to follow-up in every 3-6 months and venesection is
carried out if necessary, to maintain SF <50 mcg/L.
• Patients should advice about dietary restriction of iron rich foods or use of
PPI to reduce iron absorption.

28. Chelation Therapy
• Deferoxamine: IV/SubQ, 20–40 mg/kg/day
• Time-consuming, painful
• Deferasirox: 20 mg/kg/day orally
• Deferiprone: 25 mg/kg TID
• Used when phlebotomy not feasible (e.g., anemia, thalassemia)
• Many side effects and drug interactions

29. Surgical Options & Other Treatments
• Liver transplant: for advanced cirrhosis
• Worse outcomes due to cardiac/infectious complications
• Monitor and treat complications: Arthropathy, diabetes, heart disease,
hypopituitarism

30. Outcome & Prognosis
• ↑ Risk of infection: Vibrio, Listeria, Yersinia
• Cirrhosis → 15–20% hepatocellular carcinoma risk
• Phlebotomy alters course favorably
• May reverse varices, cardiac conduction issues
• Cirrhotics need lifelong HCC surveillance
• Post transplant 1 year survival is about 80 to 85 percent and 5 year survival
about 60 to 70 percent

31. Histopathology of HH
• Patterns of Iron Deposition
• Parenchymal Pattern (early HH):
• Iron in hepatocytes
• Fine granules, especially at biliary pole
• Gradient: periportal > centrilobular
• Mesenchymal Pattern (advanced HH):
• Iron in Kupffer cells and portal macrophages
• Occurs after hepatocyte necrosis
• Hepatocytic iron is sparse and coarse, near iron-loaded macrophages
• Mixed Pattern:
• Combination of parenchymal and mesenchymal features
• 🧠 Interpretation of pattern helps stage disease and suggests etiology

32. Scheuer Grading System

34. In late hemochromatosis, the iron
deposits in bile ducts (Arrow) /
portal area.

35. Trichrome shows bridging fibrosis with
nodule formation, indicating liver
cirrhosis. Long-term iron toxicity leads to
progressive damage to the liver and
subsequently results in cirrhosis.

36. Brief Summary of Recommendations

37. Diagnostic Recommendations
•Test for haemochromatosis if:
•TSAT >45% in women or >50% in men
•Ferritin >200 µg/L in women or >300 µg/L in men
•HFE Genotyping for p.C282Y after informed consent
•Screen first-degree relatives if proband has HFE-related haemochromatosis

38. Non-Invasive Diagnosis Tools
• Use MRI to quantify liver iron if:
• Biochemical iron overload with non-HFE genotype
• Unexplained hyperferritinemia
• Use cardiac MRI in juvenile haemochromatosis with cardiac symptoms

39. Liver Biopsy Use
•Not recommended: To confirm diagnosis
•Recommended if:
•Ferritin >1,000 µg/L
•Elevated transaminases or hepatomegaly
•Cirrhosis cannot be confirmed non-invasively

40. Fibrosis Assessment
•Assess all patients at diagnosis
•Use transient elastography (LSM <6.4 kPa rules out advanced fibrosis)
•FIB-4 can support assessment, but evidence is limited

41. Management Recommendations
• First-line treatment: Therapeutic phlebotomy
• Induction phase: Ferritin target <50 µg/L
• Maintenance phase: 50–100 µg/L
• Monitor Hb and ferritin regularly
• Consider erythrocytapheresis in select cases

42. Surveillance & Complications
• HCC screening every 6 months if:
• Cirrhosis or advanced fibrosis
• Even after fibrosis regression, continue surveillance
• Use ultrasound, consider MRI/CT if inadequate

43. Extrahepatic Manifestations
• Investigate:
• Joint disease (2nd/3rd MCP, osteoarthritis-like)
• Endocrine (diabetes, hypogonadism)
• Cardiac (especially in juvenile forms)

44. Recommendations for Rare Cases
• Young patients or those with unexplained overload: sequence non-HFE
genes
• Family screening for rare variants
• Specialist referral for uncertain diagnosis

45. Special Considerations in Pregnancy
•Avoid iron deficiency
•Individualize phlebotomy; often paused during pregnancy
•Assess for fibrosis before pregnancy

46. THANK YOU