Primary Biliary Cirrhosis & Hemochromatosis

1. Primary Biliary Cirrhosis & Hemochromatosis Aliyu Ndajiwo #605.

2. Primary Biliary Cirrhosis (PBC)

3. Background • PBC is an Autoimmune disease marked by progressive destruction of the intra-hepatic bile ducts. • Age of onset is between 20 and 80 years. • Female:male ratio is at 6:1.

4. Etiology & Pathogenesis • Expression of MHC class II molecules on bile duct epithelial cells. • Accumulation of auto-reactive T cells around bile ducts. • Lymphocytes are also prominent in the portal regions and surround damaged bile ducts.

5. A circulating IgG anti-mitochondrial antibody (AMA) is detected in >90% of patients. • Elevated serum levels of IgM and cryoproteins are found in 80 to 90% of patients.

6. Extrahepatic manifestations of autoimmunity include: • The Sicca complex of dry eyes and mouth (Sjogren syndrome), • Scleroderma, • Thyroiditis, • Rheumatoid arthritis, • Reynaud’s phenomenom, • Membranous Glomerulonephritis, • and Celiac disease.

7. Pathology Staging (Ludwig’s classification): • Stage 1 (portal stage of Ludwig): “Chronic suppurative destructive cholangitis" • Stage 2 (periportal stage) • Stage 3 (septal stage) • Stage 4 (cirrhosis)

8. Histological staging in a representative case of a patient with primary biliary. Stage 1: reveals duct-centred inflammation showing chronic nonsuppurative destructive cholangitis (black arrows). A tiny granuloma is also seen (grey arrow). Stage 2: Shows portal enlargement (arrows) with bile ductular reaction and inflammatory cell infiltration. Stage 3: Is characterized by fibrous scaring bridging portal tracts with occasional foci of bile duct loss (no bile duct identified around an artery indicated by arrow). Stage 4: Shows cirrhotic transformation.

9. Signs and Symptoms • Early-stage PBC: • Chronic fatigue • Pruritis/itchy skin • Dry eyes and mouth • AdvancedPBC: • Jaundice • Edema • Ascites  • Xanthoma, Xanthelasmata • Diarrhea 

10. Physical examination findings: • Hepatomegaly (25%) • Hyperpigmentation (25%) • Splenomegaly (15%) • Jaundice (10%) • Xanthelasmata (10%) • Sicca syndrome (50-75%): Xerophthalmia, Xerostomia.

13. Risk Factors: •Gender •Family history Possible triggers: • Infections, such as a urinary tract infection (UTI) • Hormone replacement therapy (HRT) • Smoking • Drinking • Obesity

14. Complications • Increased pressure in the portal vein (portal hypertension). • Enlarged veins (varices). • Cirrhosis • Liver cancer. • Weak bones (osteoporosis). • Vitamin deficiencies. • Memory problems. • An increased risk of other disease.

15. Diagnosis • Blood tests: • Anti-mitochondrial antibodies (AMA). • Anti-nuclear antibodies (ANA) • Elevated Gamma-Glutamyl transferase & Alkaline Phosphatase • Bilirubin • Liver biopsy

16. Treatments • Treating the disease: • Ursodeoxycholic acid (UDCA) - ( Ursodiol, Actigall, Urso). Side effects are weight gain, hair loss and diarrhea. • Liver transplant.

17. Treating the symptoms: • Fatigue - Modafinil (Provigil). • Itching - Cholestyramine (Locholest, Prevalite). Another option is rifampin (Rifadin).

18. Preventing complications • Weak bones (osteoporosis). • Vitamin deficiencies. • Liver cancer • Cirrhosis

19. Prognosis • The serum bilirubin level is an indicator of the prognosis of PBC. Bilirubin levels of 2–6 mg/dL having a mean survival time of 4.1 years, 6–10 mg/dL having 2.1 years, and levels >10 mg/dL having 1.4 years. • After liver transplant, the recurrence rate may be as high as 18% at 5 years, and up to 30% at 10 years. • Patients with PBC have an increased risk of hepatocellular carcinoma.

20. References Robbins and Cotran Pathologic Basis of Disease, 7th Edition. Kumar Abbas Fausto. Harrison’s principles of internal medicine, 16th Edition. http://www.mayoclinic.org/diseases-conditions/primary-biliary-cirrhosis/basics/definition/con-20029377. http://www.nhs.uk/Conditions/Primary-biliary-cirrhosis/Pages/Introduction.aspx. http://en.wikipedia.org/wiki/Prima ry_biliary_cirrhosis.

21. Hemochromatosis

22. Background • Hemochromatosis is characterized by the excessive accumulation of body iron. • It results from either a genetic defect or as a consequence of parenteral administration of iron (usually in form of transfusions). • It is 5-10 times more frequent in men than women. First symptoms seen between ages 40-60.

24. Etiology & Pathogenesis • HFE associated hemochromatosis is inherited as an autosomal recessive trait. • A homozygous mutation resulting in a cystein to tyrosine substitution at position 282 (C282Y) is the most common mutation. • A second relatively common HFE mutation has also been identified, this results in histidine to aspartic acid substitutionat position 63 (H63D).

25. Normally, the body iron content of 3-4g is maintained such that intestinal mucousal absorption of iron is equal to iron loss. • This amount is approximately 1mg/d in men and 1.5mg/d in menstruating women. In hemochromatosis it amounts to 4mg/d or more. • Crypt epithelial cells with mutant HFE lack the facilitating effect on TfR-dependent iron uptake, thus decreasing the regulatory iron protein in the cell.

27. In advanced disease, the body may contain 20g or more of iron that is deposited mainly in parenchymal cells of the liver, pancreas and heart. • Tissue injury will eventually occur.

28. Morphology • The morphological changes are characterised principally by: • The deposition of hemosiderin. • Cirrhosis. • Pancreatic fibrosis

29. In the Liver, iron becomes evident first as golden-yellow hemosiderin granules in the cytoplasm of periportal hepatocytes, which stain blue with prussian blue stain.

30. Hepatic iron concentration - • Normal value for Males: 200-2,400 mcg/g dry weight, Females 400-1,600 mcg/g dry weight. • Hepatic iron concentrations >3,000 mcg/g are seen when there is iron overload without cellular injury and cirrhosis. • A hepatic iron concentration >10,000 mcg/g dry weight is diagnostic for hemochromatosis.

31. Hepatic iron index - • The HII is calculated from the hepatic iron concentration by converting the concentration from mcg/g to mcmol/g dry weight and dividing by years of age. • The normal range for HII is <1.0

32. Signs & Symptoms • Early symptoms include: • Severe fatigue (74%), • Impotence (45%), • Arthralgia (44%). The most common signs at the time of presentation are: • Hepatomegaly (13%) • Skin pigmentation (bronze) • Arthritis.

33. Clinical manifestations of hemochromatosis include the following: • Liver disease • Skin bronzing or hyperpigmentation (70%) • Diabetes mellitus (48%) • Arthropathy • Amenorrhea, impotence, hypogonadism • Cardiomyopathy • Osteopenia and osteoporosis • Hair loss • Koilonychia (spoon nails)

34. Risk factors include - • Having 2 copies of a mutated HFE gene. • Family history • Ethnicity - People of Northern European descent are more prone to hereditary hemochromatosis than people of other ethnic backgrounds. • Being a Man.

35. Diagnosis & Tests • The Association of these conditions should suggest the diagnosis- • Hepatomegaly • Skin pigmentation • Diabetes Mellitus • Heart disease • Arthritis • Hypogonadism.

36. Lab tests: • Genetic testing: HFE mutations (C282Y, H63D) • Serum iron (>160mcg/dL) • Transferrin saturation levels (>55%) • Serum ferritin studies (>400ng/mL in males or >200ng/mL in females) • Hepatic iron concentration • Imaging studies: • Chest radiography and echocardiography. • CT scanning for the detection of mild hepatic iron overload. • MRI may be more sensitive than CT scanning

37. Procedures: The following are procedures that may be used to assess patients with hemochromatosis: • Diagnostic endoscopy • Skin biopsy • Liver biopsy, with biochemical determination of HIC and calculation of the HII and histologic evaluation with iron staining (Perls Prussian blue)

38. Treatment: Phlebotomy Chelation therapy- Deferoxamine, Deferasirox, Deferiprone. Surgery: Surgery is done to treat these important complications - End-stage liver disease. Hepatocellular Carcinoma Severe arthropathy. (Surgical arthroplasty)

39. Prognosis • The most important prognostic factor at the time of diagnosis is the presence or absence of hepatic fibrosis or cirrhosis. • If untreated, hemochromatosis may lead to death from • Cirrhosis • Diabetes • Malignant hepatoma (Hepato-cellular carcinoma) • Cardiac disease

40. References • Robbins and Cotran Pathologic Basis of Disease, 7th Edition. Kumar Abbas Fausto. • Harrison’s principles of internal medicine, 16th Edition. • http://www.mayoclinic.org/diseases-conditions/hemochromatosis/basics/definition/con-20023606 • http://en.wikipedia.org/wiki/Iron_overload • http://www.hemochromatosis.org/ • http://emedicine.medscape.com/article/177216-overview