inheretid liver diseases

1. Inherited Liver Diseases
Dr. Azad S. Mohammed
MBChB., FIBMS
1

2. Hereditary haemochromatosis (HHC)
 It is inherited as an autosomal recessive trait.
 Iron is deposited throughout the body. The important organs
involved are the liver, pancreatic islets, endocrine glands and
heart.
 Total body iron may reach 20–60 g (normally 4 g).
 There is macronodular cirrhosis.
2

3. Pathophysiology
 There is increased absorption of dietary iron .
 Approximately 90% are homozygous for a single-point mutation
resulting in a cysteine to tyrosine substitution at position 282
(C282Y) in the HFE protein.
 A histidine to aspartic acid mutation at position 63 (H63D) in HFE
causes a less severe form that is most commonly found in
compound heterozygotes also carrying a C282Y mutated allele.
 HHC may promote accelerated liver disease in patients with
alcohol excess or hepatitis C infection.
 Iron loss in menstruation and pregnancy can delay the onset of
HHC in females. 3

4. Clinical features
 ~ 90% of patient are male
 Usually presents in men > 40 years with features of liver disease
(often with hepatomegaly), DM or HF.
 Fatigue and arthropathy are early symptoms but are frequently
absent.
 Leaden-grey skin pigmentation due to excess melanin occurs,
especially in exposed parts, axillae, groins and genitalia: hence
the term ‘bronzed diabetes’.
 Impotence, loss of libido, testicular atrophy and arthritis with
chondrocalcinosis secondary to calcium pyrophosphate
deposition are also common.
 Cardiac failure or cardiac dysrhythmia may occur due to iron
deposition in the heart. 4

5. Investigations
1. Serum iron studies:
• High ferritin, high iron, high TIBC. They are highly variable
• Transferrin saturation of >45% is suggestive of Fe overload
• Significant liver disease is unusual in ferritin <1000 μg/L.
• DDx of high ferritin: inflammatory disease or excess ethanol
consumption, adult Still’s disease.
2. MRI has high specificity for iron overload, but poor sensitivity.
3. Liver biopsy for assessment of fibrosis and distribution of iron
 Hepatocyte iron characteristic of haemochromatosis.
 The Hepatic Iron Index (HII) provides quantification of liver iron
(μmol of iron per g dry weight of liver/age in years).
 HII of >1.9 suggests genetic haemochromatosis
4. Genetic testing for C282Y and the H63D mutations
5

6. 6
Management
1. Venesection:
 Weekly venesection of 500 mL blood (250 mg iron) until the
ferritin is 20-50 μg/L; this may take 2 years or more.
 Maintenance therapy with phlebotomy of 1 unit every 2-3 months
to keep ferritin 20-50 ng/ml.
 Liver, cardiac and skin problems improve
 Joint pain is less predictable (can improve or worsen).
 DM control become better (DM does not resolve).
 No reversal of testicular atrophy
 It reduces (does not abolish) the risk of HCC in cirrhosis

7. 7
Management
2. Iron chelating drugs:
 Indications: HFE-related HH and cardiac manifestations or in
patients who cannot tolerate phlebotomy.
 Deferoxamine is given via subcutaneous infusion.
3. Liver transplantation:
 It is indicated for complications of end-stage liver disease
 Survival rates after LT in HH are lower than LT for other causes
4. Treatment for cirrhosis and diabetes mellitus.
5. Screening for HCC is mandatory

8. 8
Management
6. Family screening:
 First degree family members should be investigated,
preferably by genetic screening and also by checking
the plasma ferritin and transferrin saturation.
 Liver biopsy is only indicated in asymptomatic relatives
if the LFTs are abnormal and/or ferritin is > 1000 μg/L
because these features are associated with significant
fibrosis or cirrhosis.
 Asymptomatic disease should also be treated by
venesection until the serum ferritin is normal.

9. 9
Prognosis
 Pre-cirrhotic patients with HHC have a normal life
expectancy
 Cirrhotic patients have a good prognosis compared with
other forms of cirrhosis (3/4 of patients are alive 5
years after diagnosis).
 This is probably because liver function is well preserved
at diagnosis and improves with therapy.
 HCC is the main cause of death, affecting 1/3 of
patients with cirrhosis irrespective of therapy.

10. 10
Wilson’s disease (WD)

11. 11
Pathophysiology
 Normally, dietary copper is absorbed from the stomach &
proximal small intestine, & in the liver, it is stored and
incorporated into ceruloplasmin, which is secreted into the
blood.
 Excessive copper is excreted via bile.
 In WD, there is almost always a failure of synthesis of
ceruloplasmin (5% have a normal circulating ceruloplasmin)
 The amount of copper in the body at birth is normal, but
thereafter it increases steadily.
 The organs most affected are the liver, basal ganglia of the
brain, eyes, kidneys and skeleton.
 The ATP7B gene encodes copper transporting proteins which
export copper from various cell types. At least 200 different
mutations have been described.

12. 12
Clinical features
 Symptoms usually arise between the ages of 5 and 45 years.
 Hepatic disease occurs predominantly in childhood and early
adolescence, although it can present in adults in their fifties.
 Neurological damage causes basal ganglion syndromes &
dementia, which tends to present in later adolescence.
 These features can occur alone or simultaneously.
 Other manifestations include renal tubular damage and
osteoporosis, but these are rarely presenting features.

13. 13
Clinical features
 Liver disease:
 Recurrent acute hepatitis can occur, especially in children,
and may progress to fulminant liver failure.
 Fulminant liver failure is characterised by the liberation of
free copper into the blood stream, causing massive
hemolysis and renal tubulopathy.
 Chronic hepatitis can also develop insidiously and
eventually present with established cirrhosis; liver failure
and portal hypertension may supervene.
 WD should be considered in any patient <40 years
presenting with recurrent acute hepatitis or CLD of
unknown cause, especially when accompanied by
hemolysis.

14. 14
Clinical features
 Neurological disease
 Extrapyramidal features, particularly tremor,
choreoathetosis, dystonia, parkinsonism & dementia
 Unusual clumsiness for age may be an early
symptom.
 Neurological disease typically develops after the
onset of liver disease and can be prevented by
effective treatment started following diagnosis in
the liver disease phase.
 This increases the importance of diagnosis in the
liver phase.

15. 15
Clinical features
 Kayser–Fleischer rings (K-F rings):
 These constitute the most important single clinical clue to the
diagnosis
 It can be seen in 60% of adults with WD (less often in children
but almost always in neurological WD)
 It is sometimes only by slit-lamp examination.
 K-F rings are characterized by greenish-brown discoloration of
the corneal margin appearing first at the upper periphery
 They disappear with treatment.

16. 16
Investigations
 Low serum ceruloplasmin is the best single laboratory clue to
the diagnosis.
 Advanced liver failure from any cause can reduce the
caeruloplasmin, and occasionally it is normal in WD.
 High free serum copper concentration
 High urine copper excretion (>0.6 μmol/24 hrs; 38 μg/24 hrs).
The 24-hour urinary copper excretion whilst giving D-
penicillamine is a useful confirmatory test; >25 μmol/24 hrs is
considered diagnostic of WD.
 Very high hepatic copper content.

17. 17
Management
1. Dietary elimination of copper-rich foods: organ meats, shellfish,
nuts, chocolate, and mushrooms.
2. D-penicillamine:
 It is a copper-binding agent & is the drug of choice.
 The dose given must be sufficient to produce cupriuresis and
most patients require 1.5 g/day (range 1–4 g).
 The dose can be reduced once the disease is in remission but
treatment must continue for life, even through pregnancy.
 Abrupt discontinuation of treatment must be avoided because
this may precipitate acute liver failure.
 Toxic effects occur in 1/3: rashes, protein-losing nephropathy,
lupus-like syndrome & bone marrow depression.

18. 18
Management
3. Potential alternatives for D-penicillamine (used when side
effects occur): trientine dihydrochloride (1.2–2.4 g/day) and
zinc (50 mg 3 times daily).
4. Liver transplantation (LT):
 It is indicated for fulminant liver failure or for advanced
cirrhosis with liver failure.
 The value of LT in severe neurological WD is unclear.
5. Siblings and children of patients with WD must be investigated
and treatment should be given to all affected individuals, even
if they are asymptomatic.
 Prognosis is excellent, provided treatment is started before there is
irreversible damage.

19. 19
Gilbert’s syndrome
 It is the most common non-hemolytic hyperbilirubinaemia, &
the most common inherited disorder of bilirubin metabolism
 Incidence is 3-7% of the population，
 Males predominate over females by a ratio of 2-7: 1
 It is inherited as an autosomal dominant trait. There are also
sporadic cases due to new mutation.
 There is a mutation in the promoter region of the UDP-
glucuronyl transferase enzyme reducing its activity.
 There is impaired conjugation of bilirubin.
 There is mild unconjugated hyperbilirubinemia, with serum
levels almost always < 6 mg/dL. Other investigations are
normal with no bilirubinuria. .

20. 20
Gilbert’s syndrome
 The typical presentation is with isolated elevation of bilirubin,
typically, although not exclusively, in the setting of physical
stress or illness
 The serum levels may fluctuate and jaundice is often identified
only during periods of fasting (fasting reduces levels of UDP-
glucuronyl transferase).
 Liver biopsy is normal (not indicated)
 Bilirubin decreases during treatment with phenobarbital (may
be used as confirmatory test in difficult cases).
 The condition has an excellent prognosis
 It needs no treatment, and is clinically important only because
it my be mistaken for more serious liver disease.

21. 21
Autoimmune Liver
and Biliary Disease

22. 22
Topics
 Autoimmune hepatitis (AIH)
 Primary biliary Cholingitis (PBC)
 Primary Sclerosing Cholangitis (PSC)
 IgG4-associated cholangitis

23. Autoimmune hepatitis (AIH)

24. 24
Pathophysiology
 It remains unclear
 Cross-reactivity with viruses such as HAV and EBV in
immunogenetically susceptible individuals (HLA-DR3 and DR4)
has been suggested as a mechanism.
 The formal classification into disease types has fallen out of
favur in recent years:
 Type-1 AIH: young adult females, high titer of ANA ,ASMA with
high IgG.
 Type-2 AIH: most are children, anti-LKM1, more resistant to
treatment than ANA-positive disease, Adult onset in HCV.
 More recently, Ab to anti-soluble liver antigen in adults often
with aggressive disease (? Type-3 AIH).

25. 25
Clinical features
 The onset is usually insidious, with fatigue, anorexia and
jaundice.
 In about ¼. the onset is acute, resembling viral hepatitis, but
resolution does not occur.
 This acute presentation can lead to extensive liver necrosis
and liver failure.
 Other features include fever, arthralgia, vitiligo, epistaxis,
amenorrhoea, lymphadenopathy
 Jaundice is mild to moderate or occasionally absent.
 Signs of chronic liver disease, especially spider naevi and
hepatosplenomegaly, can be present.
 Some patients 'Cushingoid' facies.

26. 26
Clinical features
 Associated autoimmune disease is often present (in ~2/3) and
can modulate the clinical presentation.
 They include:
 MSK: Migrating polyarthritis
 Skin: Urticarial rashes
 Endocrine: Hashimoto’s thyroiditis, Thyrotoxicosis,
Myxedema
 RT: Pleurisy, Transient pulmonary infiltrates
 Hematology: Coombs-positive hemolytic anemia
 GIT: Ulcerative colitis
 GUT: Glomerulonephritis, Nephrotic syndrome

27. 27
Investigations
 Serological tests for autoantibodies are often positive but low titers
of these antibodies occur in some healthy people and in other
inflammatory liver diseases.
 IgG are elevated but could be normal.
 ANA also occur in connective tissue diseases.
 ASMA in infectious mononucleosis and malignant diseases.
 If the diagnosis of AIH is suspected, liver biopsy should be performed
which shows interface hepatitis.

28. 28
Management
 Management of exacerbations:
 Steroids are life-saving in AIH, particularly during exacerbations
of active & symptomatic disease
 Prednisolone (40 mg/day) gradually reduced as the patient and
LFTs improve.
 Patients should be monitored for acute exacerbations
 Maintenance therapy:
 Given once LFTs are normal (& IgG if elevated)
 Prednisolone (ideally below 5–10 mg/day), usually with
azathioprine 1.0–1.5 mg/kg/day.
 Azathioprine can be given alone.
 Mycophenolate mofetil (MMF) can be used.

29. 29
Primary biliary cholangitis (PBC)

30. 30
Definition
 PBC is a chronic, progressive cholestatic liver disease that
predominantly affects middle-aged women and strongly
associated with AMA, which are diagnostic and is characterized
by a granulomatous inflammation of the portal tracts.
 There is a strong female to- male predominance of 9 : 1.
 It is also more common amongst cigarette smokers.
 Clustering of cases suggests an environmental trigger in
susceptible individuals

31. 31

32. 32
Clinical features
 It typically presents with insidious itching &/or tiredness
 It may be found incidentally from routine blood tests.
 Fatigue is common and may precede diagnosis for years.
 Pruritus is a common presenting complaint and may precede
jaundice by months or years. It is usually worse on the limbs.
 Jaundice is rarely a presenting feature. It is only prominent late
in the disease
 There may be right upper abdominal discomfort but fever and
rigors do not occur.
 Bone pain or fractures are due to osteoporosis (hepatic
osteodystrophy) or osteomalacia (fat-soluble vitamin
malabsorption).

33. 33
Clinical features
 Initially, patients are well nourished but weight loss can
occur as the disease progresses.
 Scratch marks may be found in severe pruritus.
 Xanthomatous deposits occur in a minority, especially
around the eyes.
 Mild hepatomegaly is common and splenomegaly
becomes increasingly common as portal hypertension
develops.
 Liver failure may supervene.
 Associated diseases: sicca syndrome, systemic sclerosis,
coeliac disease and thyroid diseases.

34. 34
Investigations
 The LFTs show a pattern of cholestasis
 Hypercholesterolaemia is common and worsens as disease
progresses but it is of no diagnostic value.
 AMA is present in over 95% of patients
 When AMA is absent, the diagnosis should not be made
without liver biopsy and considering cholangiography
(MRCP or ERCP) to exclude other biliary disease.
 IgM are elevated.
 ANA and ASMA are present in ~15% of patients
 Ultrasound examination shows no sign of biliary
obstruction.
 Liver biopsy is only necessary if diagnostic uncertainty.
 Poor correlation between histology and clinical features

35. 35
Diagnosis
 The diagnosis of PBC can be established when two of
the following three criteria are met:
 Biochemical evidence of cholestasis based mainly on
alkaline phosphatase elevation.
 Presence of AMA.
 Histologic evidence of nonsuppurative destructive
cholangitis and destruction of interlobular bile ducts

36. 36
Management
1. Ursodeoxycholic acid (UDCA):
 It is a hydrophilic naturally occurring secondary bile acid.
 Dose is 13–15 mg/kg/day
 It improves bile flow, replaces toxic hydrophobic bile
acids in the bile acid pool, and reduces apoptosis of the
biliary epithelium.
 Clinically, it improves LFTs, improves jaundice, may slow
down histological progression and has few side-effects
 It is the optimal first-line treatment.
 Controversial effects on mortality or transplantation rates
 A significant minority of patients either fail to normalize
their LFTs with UDCA or show an inadequate response, &
these have an increased risk of end-stage liver disease.

37. 37
Management
2. Immunosuppressants:
 Corticosteroids, azathioprine, penicillamine and ciclosporin,
have all been trailed in PBC.
 None shows overall benefit.
 Whether they benefit the UDCA non-responding patients is
not clear.
3. Liver transplantation:
 Indicated for liver failure, intractable pruritus.
 Serum bilirubin is the most reliable marker of declining liver
function.
 Excellent 5-year survival of over 80%
 It recur in over 1/3 of patients at 10 years.

38. 38
Management
4. Pruritus:
 The cause is unknown but may be up-regulation of opioid
receptors and increased endogenous opioids
 Colestyramine:
 It is first-line Rx.
 Dose is 4–16 g/day.
 It is anion-binding resin & probably acts by binding potential
pruritogens in the intestine and increasing their excretion in
the stool.
 Alternative treatments: rifampicin (150-600 mg/day), naltrexone
(an opioid antagonist; 25-300 mg/day), plasmapheresis and a
liver support device (e.g. a molecular adsorbent recirculating
system (MARS)).

39. 39
Management
5. Fatigue
 It affects 1/3 of patients.
 The cause is unknown but it may reflect intracerebral
changes due to cholestasis.
 Once depression, hypothyroidism and coeliac disease have
been excluded, there is currently no specific treatment.
6. Malabsorption
 Prolonged cholestasis causes steatorrhoea and
malabsorption of fat-soluble vitamins, which should be
replaced as necessary.
 Coeliac disease should be excluded (increased in PBC).

40. 40
Management
7. Bone disease
 Osteopenia and osteoporosis are common, and normal post-
menopausal bone loss is accelerated.
 Baseline bone density should be measured
 Replacement calcium and vitamin D3 should be started.
 Bisphosphonates should be used in osteoporosis.
 Osteomalacia is rare.

41. 41
Overlap syndromes
AMA-negative PBC (‘autoimmune cholangitis’)
 A few patients demonstrate the clinical, biochemical and
histological features of PBC but do not have detectable AMA in the
serum.
 Serum transaminases, serum Ig levels and titers of ANA tend to be
higher than in AMA positive PBC.
 The clinical course mirrors classical PBC and these patients should
be considered to have a variant of PBC.
PBC/autoimmune hepatitis overlap
 A few patients with AMA and cholestatic LFTs have elevated
transaminases, high serum immunoglobulins and interface hepatitis
on liver histology
 Trial of corticosteroid therapy may be beneficial.

42. 42
Primary Sclerosing Cholangitis
(PSC)

43. 43
Definition
 PSC is a cholestatic liver disease caused by diffuse
inflammation and fibrosis leading to gradual
obliteration of intrahepatic and extra-hepatic bile
ducts, and ultimately biliary cirrhosis.
 The generally accepted diagnostic criteria are:
 Generalized beading and stenosis of the biliary
system on cholangiography
 Absence of choledocholithiasis (or history of bile
duct surgery)
 Exclusion of bile duct cancer, by prolonged follow-
up.

44. 44
Definition
 ‘Secondary sclerosing cholangitis’ describes the typical bile duct
changes described above when a clear predisposing factor for duct
fibrosis can be identified.
 The causes of secondary sclerosing cholangitis:
 Previous bile duct surgery with stricturing and cholangitis
 Bile duct stones causing cholangitis
 Intrahepatic infusion of 5-fluorodeoxyuridine
 Insertion of formalin into hepatic hydatid cysts
 Insertion of alcohol into hepatic tumours
 Parasitic infections (e.g. Clonorchis)
 Autoimmune pancreatitis/IgG4-associated cholangitis
 Acquired immunodeficiency syndrome (AIDS; probably infective as a
result of cytomegalovirus or Cryptosporidium)

45. 45
Epidemiology
 The incidence is about 6.3/100 000 in Caucasians.
 It is twice as common in young men.
 Most patients present at age 25–40 years but may be
diagnosed at any age and is an important cause of
chronic liver disease in children.

46. 46
Pathophysiology
 The cause of PSC is unknown but there is a close
association with IBD, particularly ulcerative colitis:
 About 2/3 of patients have coexisting UC, and PSC is
the most common form of chronic liver disease in
UC.
 ~ 3-10% of patients with UC develop PSC,
particularly extensive colitis or pancolitis.
 PSC is lower in Crohn’s colitis (about 1%).
 Patients with PSC and UC are at greater risk of CRC
than those with UC alone, and those who develop
CRC are at greater risk of cholangiocarcinoma.

47. 47
Pathophysiology
 It is currently believed that PSC is an immunologically
mediated disease, triggered in genetically susceptible
individuals by toxic or infectious agents, which may
gain access to the biliary tract through a leaky,
diseased colon.
 Although considered as an autoimmune disease,
evidence for an autoimmune pathophysiology is weaker
than is the case for PBC and AIH.
 A close link with HLA haplotype A1 B8 DR3 DRW52A has
been identified.
 Perinuclear antineutrophil cytoplasmic antibodies
(pANCA) in 60–80% of PSC (in 30–40% of UC alone).
 ANCA is not specific for PSC (in 50% of AIH).

48. 48
Clinical features
 The diagnosis is often made incidentally when
persistently raised serum ALP is discovered in an
individual with UC.
 Common symptoms include fatigue, intermittent
jaundice, weight loss, right upper quadrant abdominal
pain and pruritus.
 Attacks of acute cholangitis are uncommon and usually
follow biliary instrumentation.
 Physical examination is abnormal in about 50% of
symptomatic patients; the most common findings are
jaundice and hepatomegaly/splenomegaly.

49. 49
Investigations
 Cholestatic LFTs
 ALP and bilirubin may vary widely during the course of
the disease and may fluctuate for no apparent reason.
 Modest elevations in transaminases are usually seen.
 Hypoalbuminaemia and clotting abnormalities are
found only at a late stage.
 In addition to ANCA, low titers of ANA and ASMA may be
found in PSC but have no diagnostic significance
 Serum AMA is absent.

50. 50
Investigations
 The key investigation is now MRCP, which is usually
diagnostic, revealing multiple irregular stricturing and
dilatation
 ERCP should be reserved for therapeutic interventions.
 Liver biopsy may show the periductal ‘onion-skin’
fibrosis and inflammation. Obliterative cholangitis
leads to the so-called ‘vanishing bile duct syndrome’.

51. 51
Management
 There is no cure for PSC.
 UDCA is widely used, although the evidence to support this is
limited. It reduces CRC risk.
 Immunosuppressive agents (prednisolone, azathioprine,
methotrexate and ciclosporin) have disappointing results.
 Pruritus is treated as in PBC.
 Fatigue is less prominent than in PBC but present in some
patients.

52. 52
Management
 Management of complications:
 Broad-spectrum antibiotics (e.g. ciprofloxacin) for acute
attacks of cholangitis but have no proven value in preventing
attacks.
 If cholangiography shows a (‘dominant stricture’), ERCP with
balloon dilatation or stenting is done but consider the
possibility of cholangiocarcinoma
 Fat-soluble vitamin replacement is necessary in jaundiced
patients.
 Metabolic bone disease (usually osteoporosis) is a common
complication that requires treatment

53. 53
Management
 Surgical treatment:
 Surgical resection for dominant extra-hepatic disease have a
limited role
 Orthotopic transplantation is the only surgical option in advanced
liver disease; 5-year survival is 80–90% in most centers.
 It may recur in the graft and there are no identified therapies
able to prevent this.
 Cholangiocarcinoma is a contraindication to transplantation.
 CRC risk can be increased in after transplantation because of the
effects of immune suppression and enhanced surveillance should
be instituted.

54. 54
Prognosis
 The course of PSC is variable.
 In symptomatic patients, median survival from presentation to
death or liver transplantation is about 12 years.
 About 75% of asymptomatic patients survive 15 years or more.
 Most patients die from liver failure, about 30% die from bile
duct carcinoma, and the remainder die from colonic cancer or
complications of colitis.
 Cholangiocarcinoma develops in 10–30%.

55. 55
IgG4-associated cholangitis
 It is closely related to autoimmune pancreatitis (which is
present in >90% of the patients).
 It often presents with obstructive jaundice (due to either hilar
stricturing/ intrahepatic sclerosing cholangitis or a low bile
duct stricture)
 Cholangiographic appearances suggest PSC with or without
hilar cholangiocarcinoma.
 The serum IgG4 is often raised
 Liver biopsy shows a lymphoplasmacytic infiltrate, with IgG4-
positive plasma cells.
 It respond well to steroid therapy.

56. 56
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