Oxford Handbook of Clinical Immunology and Allergy (3 edn)
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Primary biliary cirrhosis (PBC)
Presentation
PBC is a disease of older women (90% of patients are female).
Clinical features include initially:
profound fatigue starting in the prodrome
intense itch
arthralgia.
With disease progression:
hepatosplenomegaly
xanthelasma
skin pigmentation
eventually hepatic decompensation with jaundice.
The disease is strongly associated with other autoimmune diseases, including Sjögren’s syndrome, thyroid disease, cryptogenic fibrosing alveolitis, CREST (calcinosis, Raynaud’s, oesophageal dysmotility, sclerodactyly, and telangiectasia), and renal tubular acidosis.
Other autoimmune diseases (any type) occur more rarely.
Immunogenetics
No specific genetic linkages identified (familial occurrence is uncommon).
Cause unknown, but epidemiological work on clusters of disease suggests a possible infectious aetiology.
It is particularly common in the northeast of England.
Immunopathology
Not strictly a cirrhotic disease, as the primary pathology is inflammation around the portal triads (intrahepatic bile ducts), leading eventually to fibrosis.
Occasional overlap patients occur with features of PBC and also of chronic autoimmune hepatitis.
Increased HLA-DR expression on the biliary epithelium and an infiltrate of CD4+ T cells specific for biliary epithelial antigens.
An excess of IgM-producing B cells is seen around the biliary ducts.
Diagnosis (see Box 8.1)
LFTs show elevated alkaline phosphatase. Caeruloplasmin, lipoproteins, and cholesterol are also raised.
Biopsy shows typical features.
Total IgM levels are polyclonally raised, often significantly (20–30g/L), although the reason for this is not known.
Occasionally small monoclonal bands will be seen on electrophoresis.
Autoantibodies are diagnostic.
| Tests for diagnosis . | Tests for monitoring . |
|---|---|
FBC | FBC |
LFTs | LFTs |
Caeruloplasmin | Caeruloplasmin |
Cholesterol and lipoproteins | Cholesterol and lipoproteins |
CRP/ESR | CRP/ESR |
AMAs (also check for other organ-specific autoantibodies, TPO, GPC, true centromere) | Serum immunoglobulins and electrophoresis |
M2 antibodies | |
HEp-2 cell screen (Nsp-1, Nsp-2, gp210, laminin B receptor) | |
Serum immunoglobulins and electrophoresis |
| Tests for diagnosis . | Tests for monitoring . |
|---|---|
FBC | FBC |
LFTs | LFTs |
Caeruloplasmin | Caeruloplasmin |
Cholesterol and lipoproteins | Cholesterol and lipoproteins |
CRP/ESR | CRP/ESR |
AMAs (also check for other organ-specific autoantibodies, TPO, GPC, true centromere) | Serum immunoglobulins and electrophoresis |
M2 antibodies | |
HEp-2 cell screen (Nsp-1, Nsp-2, gp210, laminin B receptor) | |
Serum immunoglobulins and electrophoresis |
Autoantibodies
Typical immunological features are the presence of mitochondrial antibodies, found in 96% of cases.
A variety of different mitochondrial antibody patterns are identifiable (with difficulty!) by immunofluorescence (see Chapter 18 for descriptions).
The M2 pattern is most commonly associated with PBC.
M2 autoantigens have now been identified as trypsin-sensitive molecules on the inner mitochondrial membrane.
Primary antigen is the large multimeric 2-oxo-acid dehydrogenase complex, pyruvate dehydrogenase complex (PDC).
M2a recognizes the E2 subcomponent (dihydrolipoamide acyltransferase) of PDC (95% of PBC).
M2c recognizes the E2 antigen of oxoglutarate dehydrogenase (OGDC) (39–88% of PBC) and branch-chain 2-oxo-acid dehydrogenase (BCOADC) (54%), and the protein X component of PDC (95%).
M2d and M2e antigens are the E1-α and E1-β? components of PDC (41–66% and 2–7%, respectively).
Solid-phase assays are available for M2 antigens and should be used to confirm the specificity of antibodies identified by immunofluorescence.
Antibodies recognize conserved epitopes on related proteins found in fungi and bacteria.
Antibodies, which are mainly IgM and IgG3, are known to inhibit enzyme function and may penetrate viable cells.
Other antibodies have been thought to identify subgroups of PBC.
M9 antibody (anti-glycogen phosphorylase) may be a marker for early PBC with a benign prognosis (also found in low titres in healthy individuals).
M4 antibody may be a marker of aggressive disease (anti-sulphite oxidase).
Non-M2 anti-mitochondrial antibodies (AMAs) are found in myocarditis, SLE, syphilis, and some drug reactions.
Antinuclear antibodies are also found in PBC: HEp-2 cells may show multiple nuclear dots (MND) and perinuclear staining.
MND–ANA (Nsp-1, Nsp-2) are found in 10–44% of PBC patients, especially associated with Sjögren’s syndrome. The Nsp-1 antigen is p80-coilin. Nsp-2 antigen is Sp100 (pseudo-centromere). Both may occur in the absence of AMA, but it is not clear whether this subgroup is clinically different.
As CREST may also be associated with PBC, true centromere antibodies may be found (very confusing!). The presence of true anti-centromere antibodies in PBC is prognostic for portal hypertension.
Punctate perinuclear staining is due to autoantibody to the major glycoprotein of nuclear pores (gp210, found in up to 27%) and laminin B receptor. Both may occur in AMA-negative PBC. Antibodies to gp210 are associated with higher mortality and poorer outcome.
Antibodies to p62 (nucleoporin) are more frequent in stage IV disease and are associated with more severe disease.
Antibodies to carbonic anhydrase II have been identified in mitochondrial antibody negative and positive PBC.
Treatment
Treatment with immunosuppressive drugs has been thought to be unhelpful, but a trial of rituximab is now under way.
Colchicine and penicillamine have both been tried with limited benefit.
Ursodeoxycholic acid may improve symptoms but does not alter the prognosis.
Colestyramine is used to relieve itch.
Transplantation is used for endstage disease.
Autoimmune hepatitis
Presentation
Before a diagnosis of autoimmune hepatitis can be made, it is important to exclude other causes:
toxic (alcohol, drugs)
metabolic diseases (Wilson’s disease, haemochromatosis, α1-antitrypsin deficiency)
viral causes, although there is a complex link between autoimmune hepatitis and HCV.
Predominantly a disease of younger women (90% of patients are female).
May present with acute hepatitis, jaundice, profound malaise and fatigue, and amenorrhoea in women (?autoimmune).
May be marked extra-hepatic features: vitiligo and alopecia, thyroid disease, pernicious anaemia, type I diabetes mellitus, autoimmune haemolytic anaemia and ITP, rheumatoid arthritis, ulcerative colitis, glomerulonephritis, cryptogenic fibrosing alveolitis, and coeliac disease.
Immunogenetics
There is a strong association with HLA-B1, B8, DR3, DR4.
Immunopathology
Major features are piecemeal necrosis of hepatocytes in the periportal region.
There is an infiltrate of CD4+ T cells and B cells.
Later stages of the disease show typical cirrhosis.
Diagnosis (see Box 8.2)
LFTs show markedly elevated transaminases.
Prothrombin time may be prolonged in late disease.
Markers of hepatitis virus infection are absent.
Polyclonal hypergammaglobulinaemia (mainly IgG and IgA).
| Tests for diagnosis . | Tests for monitoring . |
|---|---|
FBC | FBC |
LFTs + GGT | LFTs + GGT |
Autoantibody screen (ANA, SMA, AMA, GPC, TPO) | Clotting studies |
SLA, LC-1 | Serum immunoglobulins and electrophoresis |
Liver biopsy | |
Clotting studies | |
Serum immunoglobulins and electrophoresis |
| Tests for diagnosis . | Tests for monitoring . |
|---|---|
FBC | FBC |
LFTs + GGT | LFTs + GGT |
Autoantibody screen (ANA, SMA, AMA, GPC, TPO) | Clotting studies |
SLA, LC-1 | Serum immunoglobulins and electrophoresis |
Liver biopsy | |
Clotting studies | |
Serum immunoglobulins and electrophoresis |
Autoantibodies
Antibodies to HCV or HCV PCR+ = exclusion criteria for autoimmune hepatitis!
Type 2b hepatitis is associated with antibodies to hepatitis C in addition to the LKM antibodies.
Autoantibodies to nuclear components, dsDNA, smooth muscle (anti-actin), LKM antibodies, and liver membranes can be detected.
Low-titre AMA may also be detected.
The pattern of antibodies present has led to a classification scheme for autoimmune hepatitis.
Autoimmune hepatitis type 1 (AIH-1) is ANA+, smooth muscle antibody (SMA)+, P-ANCA+, and soluble liver antigen (SLA) antibody+.
In AIH-1, 50% are ANA+/SMA+, 15% are ANA+ only, and 35% are SMA+ only.
8% of AIH-1 are SLA+ only.
Typically occurs in adults, has a better prognosis, and responds well to therapy; 90% female.
High frequency of extrahepatic features.
Previously known as lupoid hepatitis.
Autoimmune hepatitis type 2a (AIH-2a) is typically liver–kidney microsomal (LKM-1, LKM-3) antibody+ and liver cytosol (LC-1) antibody+.
43% of AIH-2 are LC-1+ only.
AIH-2a is seen in children (50% of cases) and has a worse prognosis with poor response to therapy.
Associated with thyroid and gastric parietal cell autoimmunity.
Hypergammaglobulinaemia is less marked; IgA is usually low.
Autoimmune hepatitis type 2b (AIH-2b).
HCV-associated; HCV-RNA positive, antibodies to HCV positive.
No female predominance; occurs in over-40s; milder disease.
No extra-hepatic features.
LKM-1 positive (NB: HCV antigen cross-reactive with P450 (IID6) cytochrome).
Autoimmune hepatitis type 3 (AIH-3) is ANA–, LKM–, SLA+. SMA and AMA are seen less commonly.
Most patients are women (90%) and have a similar presentation to that of type 1.
Autoimmune hepatitis type 4 (AIH-4).
Overlap syndrome of autoimmune hepatitis and PBC; AMA positive with antibodies to M2 antigen.
There are cases of biopsy-proven but serologically negative hepatitis.
Tests for both SLA and LC-1 should be performed.
LKM-1 antibodies recognize the cytochrome P450IID6 and are associated with types 2a and 2b autoimmune chronic active hepatitis.
Other autoantibodies in hepatitis
Liver–kidney microsomal antibodies may be found in autoimmune hepatitis and recognize different hepatic cytochrome enzymes.
LKM-1: cytochrome P450 (IID6). associated with types 2a and 2b autoimmune hepatitis. Antibodies to LKM-1 may be triggered by HCV and HSV as both have proteins sharing homology with P450 (IID6).
LKM-2: cytochrome P450 (IIC9). Drug-induced, tienilic acid, in France only.
LKM-3: glucuronyl transferase. Hepatitis delta infection. These antibodies are specific to human liver.
Liver microsome antibodies (LM): cytochrome P450IA2. Drug-induced hepatitis, dihydralazine.
SLA antibodies recognize liver cytokeratins 8 and 18.
LC antibodies may recognize arginosuccinate lyase (and at least one other cytosolic antigen).
Treatment
Prognosis depends on type and early diagnosis.
Treatment depends on the underlying cause.
Treat any viral trigger (HCV) with α-IFN ?± ribavirin.
Immunosuppressive therapy with corticosteroids (high dose) is used and a good initial response defines a good prognosis.
Azathioprine is useful for maintaining remission.
Ciclosporin and tacrolimus have also been used.
Liver transplantation may be required for endstage disease in young patients.
Primary sclerosing cholangitis
An inflammatory disease of intra- and extra-hepatic bile ducts, leading to fibrosis.
More common in men than women and can occur at any age.
Associated with HLA-A1, B8, DR3.
May lead to cholangiocarcinoma.
Strongly associated with inflammatory bowel disease (see Chapter 7).
LFTs are similar to those for PBC.
Anti-mitochondrial antibodies are absent, the IgM is not raised, and atypical P-ANCA may be found. P-ANCA is present in about 80% of cases.
Anti-nuclear and anti-smooth muscle antibodies may be present in 25–50% of cases.
Diagnosis is made by endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP).
Immunosuppressive treatment is unhelpful. Liver transplantation may be required.
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