Hemochromatosis 

(Classic trade: cirrhosis,  DM, skin pigmentation)

 

• Haemochromatosis:

• • Iron overload in parenchymal cells leading to organ dysfunction

• Hemosiderosis: 

• • Iron deposition in reticuloendothelial cells with no organ dysfunction 

 

 

Pathophysiology:

 

There is increased iron absorption from duodenum

↓

Total body iron is increased (20-60 g; Normal 4 g)

↓

Excess iron is deposited in

• • • • • Liver
        • Pancreatic islets
        • Endocrine glands
        • Joints
        • Heart

     

 

Types:

1. Primary (hereditary)
2. Secondary iron overload (acquired)

 

 

Primary (Genetic Hemochromatosis )

 

Clinical features (C/F):

• Male 90% (iron loss in menstruation and pregnancy may protect female)
• Age: >40 years 
• Tiredness, fatigue, 
• Liver: Signs of liver disease ( often hepatomegaly) 
• Pancreas: Diabetes mellitus
• Heart: Heart failure, arrhythmia 
• Skin pigmentation:  (Bronze diabetes)         
  • Leaden gray skin pigmentation→ exposed parts, axillae, groins, genitalia

• Endocrine gland: 
  • Impotence, loss of libido, testicular atrophy (due to pituitary infiltration) 
• Joints: 
  • Arthropathy, 
  • Early onset osteoarthritis -MCP joint, 
  • Chondrocalcinosis, pseudogout
    • due to calcium pyrophosphate deposition,
    • both large and small joint

 

 

Investigations:

 

Investigation	Finding/justification
Iron profile:	Serum ferritin: increased ( >1000 ug/L) Plasma iron: increased Transferrin saturation: high (women >40%, men >50%) TIBC- reduced
ESR, CRP	to exclude inflammatory condition
Molecular testing for HFE mutation
AST, ALT	if elevated, risk of liver disease
Transient elastography	For fibrosis assessment If ALT, AST elevated, ferritin >1000
Hepatic MRI	Iron assessment
Liver biopsy with Perls staining	Iron deposition within hepatocytes→ Genetic Hemochromatosis (GH) within reticuloendothelial cells →2ndry iron overload  Hepatic Iron Index (HII) > 1.9 → GH Stage of fibrosis/cirrhosis

 

 

Management:

• Venesection: 500 ml of blood (250 mg iron) weekly
  • Target: ferritin <50 ug/L, TSat < 50% (may take 2 years / more)
  • Then continued as required

• Treatment of cirrhosis, diabetes, heart failure, arrhythmia, joint pain etc
• Family screening (first degree): 
  • Genetic screening**
  • Plasma ferritin and transferrin saturation
  • LFTs
  • Liver biopsy: if LFTs are abnormal / serum ferritin > 100 μg/l
  • Treatment: venesection

 

 

Prognosis:

• Pre-cirrhtic patients have normal life expectancy
• Cirrhotic patients have good prognosis: 3/4 alive 5 years after diagnosis
• 1/3 patients with cirrhosis develops HCC (cause of death, need regular screening)

 

 

Follow Up:

• Screening for hepatocellular carcinoma 

 

                       

 

Secondary Hemochromatosis (Acquired)

 

Causes:

• Multiple blood transfusions (> 50 liters) in 

• Chronic hemolytic disorders (thalassemia), 
• Sideroblastic anaemias & others

• Porphyria cutanea tarda
• Dietary iron overload
• ALD
• NAFLD, 
• Hepatitis C    

                                                   

** Some patients are heterozygotes for the primary haemochromatosis gene and this may contribute to the development of iron overload

 

** Why impotent?

1. Hypogonadism-Pituitary dysfunction, 
2. Erectile failure- diabetic autonomic neuropathy/ vascular disease 

 

 

Other Inherited liver disease: Wilson disease

 

 

 

Self Assessment

SAQ. A 40-year-old diabetic man presented with shortness of breath which is more on lying position for 5 days. He has no history of Asthma, COPD or IHD. He was also suffering from pain in metacarpophalangeal joints for 2 months. He felt extremely fatigue all the time. On examination the patient has jaundice, hepatomegaly and pigmentation in axilla and groins.

 

Q. What is the most likely Diagnosis

• • Haemochromatosis with DM (bronze diabetes) with
  • Heart failure with early onset OA with (?) CLD

 

Q. Outline The management options

• Weekly Venesection of 500 ml blood to reduce 
  • transferrin saturation below 50%. 
• Liver and cardiac problems improve after venesection but diabetes does not resolve.
• Screening of Family Member
• Regular follow up for Hepatocellular Carcinoma.

 

Q. What are the complications of the condition.

• Apart from heart failure, early onset OA,
• Pituitary/gonadal failure: testicular atrophy, loss of libido, 
• Other complications of CLD such as Hepatic encephalopathy.

 

 

SAQ. A 56 year old lady is hospitalized with complaints of weakness, loss of appetite, palpitation and severe pain in both knee joints for 6 months. She is also complaining of recurrent syncopal attack. On examination, she looks pigmented and emaciated. anemia- moderate, no jaundice, mild edema. BP-100/60 mmHg on lying, 80/50 mmHg on standing, pulse-120/ min, irregularly irregular. 

• Liver- palpable,4 cm, nontender, firm in consistency. No splenomegaly. 
• Investigations: FBC: Hb- 8.3 gm/dl, WBC- 6800/cmm, RBS- 13.1 mmol/l, CXR- cardiomegaly, ECG- multiple ventricular ectopics. S. cortisol- 110 nmol/l (normal: 170-720), S. TSH-0.12 mIU/I (normal: 0.5-5.1), S. Electrolytes: Na- 123, k-4.7, Cl- 92, S. Creatinine 1.2 mg/dl.

 

Q.1. What is your diagnosis?

• Haemochromatosis with HF/Cardiomyopathy with 
• DM with Hypopituitarism with postural drop with Hyponatremia with 
• Bilateral knee joints chondrocalcinosis

 

Q.2. How will you Investigate this patient?

• For primary diagnosis:
  • LFT 
  • Iron profile (ferritin >1000, iron increased, T. sat > 45%)
  • MRI of liver
  • Liver biopsy with HII
  • Genetic testing

 

Q.3. Mention 2 reversible and 3 non reversible complications.

• Reversible: 
  • Liver disease (Hepatitis, abnormal liver function test) but not cirrhosis
  • Cardiac problem (Heart failure, Cardiomyopathy, cardiac arrhythmia)
  • Skin pigmentation

 

• Non-reversible:
  • DM 2, Hypogonadism, Arthropathy, cirrhosis

 

Q.4. Indications of liver biopsy in Haemochromatosis.

• Asymptomatic relatives with abnormal liver function 
• S. Ferritin >1000 microgram/l
• For assessment of fibrosis
• To see distribution of iron