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Primary Biliary Cirrhosis And Autoimmune Hepatitis

Other Antibodies Associated With Aih

Autoimmune Hepatitis and Primary Biliary Cholangitis | Gina Choi, MD | UCLA Digestive Diseases

Anti-Liver Cytosol Type 1 Antibodies

Anti-LC1 antibodies directed against liver cytosol 1 target epitopes of the enzyme formiminotransferase cyclodeaminase . They are present in about 30% of type 2 AIH patients, alone or in combination with anti-LKM-1 . In IFT, anti-LC1 stain hepatocytes but spare the centrilobular areas of the liver. By contrast, anti-LKM-1 stain hepatocytes throughout the liver lobule. When both antibodies are coexistent, anti-LKM-1 cover the spared areas of anti-LC1. Thereby, anti-LKM-1 can mask the presence of anti-LC1. Solid-phase assays help to identify anti-LC-1 . When anti-LC1 are the sole antibodies being detected, they strongly support the diagnosis of type 2 AIH. However, anti-LC1 are not AIH specific and can also be detected in patients with HCV .

Antineutrophil Cytoplasmatic Antibodies With a Perinuclear Staining Pattern

The presence of p-ANCA can support the diagnosis of AIH, especially in the absence of other autoantibodies . However, p-ANCA can also be detected in chronic viral hepatitis, inflammatory bowel disease , PSC or microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis . p-ANCA mainly react with myeloperoxidase. Atypical p-ANCA , which are characterized by the retention of a perinuclear staining on formaldehyde-fixed neutrophils seem to be more specific for autoimmune liver diseases and IBD .

Anti-Asialoglycoprotein Receptor Antibodies

What Are The Signs And Symptoms Primary Biliary Cholangitis

PBC may progress slowly and many people do not have symptoms, particularly in the early stages of the disease. The most common initial symptoms are fatigue and itching of the skin . Other symptoms may include:

  • Abdominal pain
  • Darkening of the skin
  • Small yellow or white bumps under the skin or around the eyes
  • Individuals may also complain of having dry mouth and eyes, and bone, muscle and joint pain.
  • As the disease progresses, symptoms of cirrhosis can develop including:
  • Yellowing of the skin
  • Swelling of the legs and feet
  • Enlarged abdomen from fluid accumulation
  • Internal bleeding in the upper stomach and esophagus from enlarged veins

Thinning of the bones leading to fractures is another complication of PBC. While this is more common in late stages of the disease, it can occur earlier as well. In addition, people with cirrhosis are at increased risk for liver cancer .

Role Of Autoimmunity In Primary Biliary Cirrhosis

Correspondence to: Feng-Chun Zhang, MD, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, No. 41 Da Mu Cang, Western District, Beijing 100032, China.

Telephone: +86-10-88068795 Fax: +86-10-88068794

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Cytokine Production By Hlcs In Nodc3c4 Mice

To further characterize the HLCs from NOD.c3c4, we measured cytokine production and compared this with production by lymph node or splenic cells from the same animal . Ribonuclease protection analysis demonstrated considerable production of IL-4, IL-5, IL-10, and IL-13 mRNA only in stimulated NOD.c3c4 HLC CD4+ cells and not in peripheral CD4+ lymph node cells from the same animal . HLCs stimulated with anti-CD3 and anti-CD28 demonstrated abundant IL-4 protein production, whereas lymph node and splenic cells from the same animal produced none . To further characterize the cellular source of HLC cytokine production, we fractionated the total HLC population into CD4+ and CD8+ populations and assayed cytokine production by each after stimulation with anti-CD3 and anti-CD28 mAbs . CD4+ T cells in the HLC population were clearly the source of almost all IFN-γ and IL-2 production .

Portal Hypertension And Esophagogastric Varices

Primary biliary cirrhosis and autoimmune hepatitis 20120902

Nodular regenerative hyperplasia is a condition characterized by hepatocytic nodules distributed throughout the liver without perinodular fibrosis and caused by occlusion of small portal veins in the portal tracts. In patients with PBC, NRH may contribute to development of non-cirrhotic portal hypertension . We have shown that patients with PBC and PSC that have a platelet count < 200,000/mm3, an albumin level < 40 g/l, and a bilirubin level > 20 micromol/l should be screened for esophageal varices . Once patients are found to have moderate to large esophageal varices, beta-blockers and/or endoscopic variceal ligation should be instituted for primary prevention of variceal bleeding . However, nonselective beta-blockers are ineffective in preventing the development of varices in unselected patients with cirrhosis . There is a report showing earlier recurrence of esophageal varices, following endoscopic therapy, in patients with PBC compared with non-PBC patients .

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Ama In Patients With Aih

Since IFT on the abovementioned rodent tissues allows the simultaneous detection of autoantibodies for different autoimmune liver diseases, PBC-specific AMA are occasionally detected during the diagnostic workup for AIH. In this case, a variant syndrome of AIH with features of PBC should be suspected, often indicated by persistent elevation of cholestatic liver enzymes after the AIH component has reached remission. In some rare cases, AMA develop during the course of classical AIH with a novel elevation of cholestatic liver enzymes . In other rare instances, AMA can be detected in AIH patients without any other laboratory or histological signs of concomitant PBC. It is unclear whether this is an epiphenomenon, whether these cases represent a subform of AIH or a very early stage of an AIH variant syndrome with additional PBC . Additional treatment with UDCA should be decided upon on an individual basis. In acute AIH, AMA may be present as an unspecific sign of acute liver damage, and they usually disappear over time .

Autoantibodies In Autoimmune Liver Diseaseclinical And Diagnostic Relevance

  • 11st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
  • 2Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

Testing for liver-related autoantibodies should be included in the workup of patients with hepatitis or cholestasis of unknown origin. Although most of these autoantibodies are not disease specific, their determination is a prerequisite to diagnose autoimmune hepatitis and primary biliary cholangitis , and they are components of the diagnostic scoring system in these diseases. In primary sclerosing cholangitis , on the other hand, autoantibodies are frequently present but play a minor role in establishing the diagnosis. In PSC, however, data on antibodies suggest a link between disease pathogenesis and the intestinal microbiota. This review will focus on practical aspects of antibody testing in the three major autoimmune liver diseases AIH, PBC, and PSC.

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Antineutrophil Cytoplasmic Antibodies With Perinuclear Staining Pattern

Usually, p-ANCA are demonstrated on IFT on alcohol-fixed human granulocytes. However, an experienced technician is required as evaluation of the staining patterns is challenging . The atypical pattern frequently found in sera of patients with PSC is characterized by broad inhomogeneous rim-like staining of the nuclear periphery and multiple intranuclear fluorescent foci. By contrast, classical p-ANCA with fine rim-like staining of the perinuclear cytoplasm are predominantly found in patients with microscopic polyangiitis .

The principal target antigen of p-ANCA is a matter of debate but is likely located within the cell nucleus rather than in the cytoplasm . The most likely candidate antigen is beta-tubulin isoform 5 . Interestingly, p-ANCA cross-react with FtsZ, which is considered an evolutionary ancestor of TBB-5 and is widely abundant in bacteria of the human intestine . This highlights that abnormal immune responses to commensal bacteria might be implied in the pathogenesis of PSC.

Both cytoplasmic ANCA and p-ANCA were also found in bile fluid of patients with PSC and correlated with several adverse clinical outcomes, which might further underline their pathogenetic significance .

B Cells And Plasma Cells

Primary Biliary Cirrhosis

Plasma cells that originate from B cells are sources of antibodies. As antigen presentation cells, B cells can secrete many kinds of cytokines and present costimulatory signals to active antigen-specific T lymphocytes. Migita et al found that serum B-cell-activating factor levels were significantly higher in PBC patients than in healthy controls and HCV-infected patients, and were positively correlated with aspartate amino-transferase and total bilirubin levels. In liver, CD5+ and CD20+ cells were associated with BEC damage, suggesting that B cells have a role in regulating the portal destruction in PBC. Therefore, B cell depletion therapy might be an alternative to UDCA. In murine experiments, IgNOD.c3c4 mice demonstrated a decreased number of activated NK cells in the liver. The degree of granuloma formation, bile duct destruction, and salivary gland histology were also shown to be significantly attenuated. Moreover, anti-CD20 therapy every 2 wk in transforming growth factor-beta receptor II dominant negative mice at age of 4-6 wk could reduce the number of B cells and CD8+ T cells in liver. In clinical therapy, two doses of 1000 mg rituximab separated by 2 wk were safe and effective in patients with an incomplete UDCA response. After treatment, not only did serum levels of total IgG, IgM, and IgA decrease significantly, but T regulatory cells also increased, which was associated with increased mRNA levels of forkhead box 3 and TGF- in CD4+ T cells.

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How Do Doctors Diagnose Primary Biliary Cholangitis

To diagnose PBC, a doctor will ask about your medical and family history, do a physical exam, order blood tests and other medical tests. Doctors use a blood test to look for a specific substance in the blood called anti-mitochondrial antibody . The presence of this substance almost always confirms PBC. Other blood test results in patients with PBC may reveal higher than normal levels of liver enzymes and higher levels of cholesterol and triglycerides. Blood work, specific for liver disease, will also be checked.

If you do have PBC, your doctor may also use an ultrasound test, which provides images of the liver and the bile ducts. Ultrasound enables doctors to see any other abnormal findings in the liver. Sometimes, a doctor will perform a liver biopsy to confirm the diagnosis. In this test, your doctor removes a small piece of the liver using a small needle and looks at it under a microscope.

Cell Purification And Stimulation

CD4+ or CD8+ cells were prepared by magnetic separation using a MiniMACS system . In brief, splenocytes were incubated with anti-CD4 or anti-CD8 magnetic microbeads for 15 min, washed, and collected on a magnetic flow-through column. Purified cells were stimulated as described previously . In brief, cells were suspended in complete medium consisting of RPMI 1640 supplemented with 10% FCS, 1 mM l-alanyl-glutamine , 100 U/ml penicillin, 100 μg/ml streptomycin , 1 mM sodium pyruvate , and 50 μM 2-ME. Cells were then transferred to 24-well plates precoated with anti-CD3 antibody, and 1 μg/ml anti-CD28 antibody was added to each well. The cells were cultured for 72 h at 37°C in a humidified 5% CO2 atmosphere. The supernatants were collected at the end of culture and stored at â80°C.

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Quick Answers For Clinicians

Antimitochondrial M2 antibodies are present in the serum of > 90% of patients with primary biliary cholangitis , and antinuclear antibodies are often present. Serum antibodies are detected via enzyme-linked immunosorbent assays or other immunoassays. The diagnostic performance characteristics of these assays and results may not be commutable. Positive results for ANAs using solid-phase immunoassays are generally meaningless, as PBC-relevant ANA patterns can only be observed via immunofluorescence antibody assays. Immunoassays for detecting specific ANAs are important for confirmation.

Although liver biopsy is no longer recommended for the majority of patients with primary biliary cholangitis , specificity issues may arise with antimitochondrial M2 antibodies and antinuclear antibodies . Thus, histology may be needed if liver biochemistry tests, autoantibody tests, and imaging fail to establish a diagnosis of PBC or are equivocal. Histology is also useful to establish diagnosis in overlap syndromes, such as PBC/autoimmune hepatitis .

Although earlier detection and intervention have reduced the need for liver transplantation in patients with primary biliary cholangitis , the British Society of Gastroenterology recommends consideration of liver transplantation in all patients with bilirubin > 50 µmol/L or with pruritus that is refractory to all medical therapy.

Treatments Aimed At Slowing Disease Progression

Primary biliary cirrhosis and autoimmune hepatitis 20120902

Many drugs have used in an attempt to improve prognosis in PBC. These can be broadly divided into two groups of agent, namely exogenous hydrophilic bile acids and immunosupressants. The best studied and most successful of these has been UDCA.

UDCA is a strongly hydrophilic bile acid which is absorbed in the terminal ileum as part of the physiological enterohepatic recirculation. Prolonged treatment results in UDCA replacing a significant proportion of biliary bile acids. The exact mechanism for the action of UDCA is unknown but it is thought to act both by replacing more hepatotoxic hydrophobic bile acids in the bile acid pool and as a choloretic agent stimulating increased biliary flow and reducing stagnation. In addition, UDCA has been reported to modify biliary epithelial HLA expression and may therefore have a local immunosuppressant action.

There has been debate as to whether the biochemical improvement predicts a true improvement in survival . This controversy has recently been highlighted by the publication of the preliminary results of a thorough meta-analysis which failed to find any survival benefit for UDCA.

UDCA has a small beneficial effect on pruritus , but little effect on fatigue.A small number of patients suffer a paradoxical increase in pruritus with UDCA which may necessitate stopping treatment. UDCA does not modify the course of associated autoimmune diseases.

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Overlap And Outlier Syndromes

A sizeable percentage of cases of autoimmune liver disease that generally fit into one diagnostic category will show clinical, serologic, or histologic features more characteristic of another type of autoimmune liver disease. When overlap in all three areas is present, the diagnosis of an overlap syndrome should be considered. However, it should be noted that it is controversial whether these overlap syndromes are distinct entities or variants of the major autoimmune hepatopathies, and standardization of diagnostic criteria and terminology is lacking.

The term overlap syndrome is used primarily to describe variant forms of autoimmune liver disease that present with both cholestatic and hepatitic features that do not fit readily into the usual diagnostic categories,, and which generally have overlapping characteristics of AIH+PBC or AIH+PSC .

Table 6 Variants of autoimmune liver disease

Evidence for a PSC-PBC overlap syndrome is limited and based upon case reports.

When To Start Treatment

Treatment should be started in patients with significant disease, characterized by at least one of the following: AST or ALT > 10 times the upper limit of normal AST or ALT > 5 times the upper limit of normal and IgG > 2 times the upper limit of normal bridging necrosis or multiacinar necrosis on histology. Although uncommon, the presence of incapacitating symptoms has also been proposed as an indication of treatment regardless of laboratory values.

In asymptomatic patients with AST, ALT, and gamma globulins/IgG elevations that do not meet the criteria above, the benefit of treatment is less clear. The course of the disease in such patients has not been well established and there is little data to support treatment. Thus in asymptomatic patients with only mild laboratory and histological changes, the decision to start treatment should be individualized and the risks of therapy taken into account. Often treatment in this situation can be postponed and liver tests followed closely. Such patients should always be referred to a hepatologist or gastroenterologist for decision regarding therapy.

Asymptomatic patients with inactive disease on liver biopsy or burned out cirrhosis do not benefit from treatment.

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Comparable Liver Histology In Nodc3c4 Mice And Pbc

We previously identified lymphocytic infiltrates around biliary epithelium in 44% of 8-wk-old and 71% of 16-wk-old NOD.c3c4 mice . Using immunohistochemistry, we identified these as predominantly CD3+ T cell infiltrates. These infiltrates were not adjacent to hepatocytes , but rather adjacent to biliary epithelial cells , consistent with direct interaction of T cells with biliary epithelial cells. Further immunohistochemical analysis demonstrated that the peribiliary CD3+ cells were comprised of cells from CD4+ and CD8+ lineages . Moreover, NOD.c3c4 peribiliary regions, but not those of control strains, demonstrated infiltrating pDCA1+ dendritic cells .

We further analyzed the HLC population in NOD.c3c4 mice by comparison with that of biliary disease-free NOD, 1803, and B6.G7 mice. The composition of the HLC populations differed markedly from that of spleen or lymph nodes due to an increased percentage of NK, γ-δ T cells, and NKT cells, although the proportions of cell subsets in pre-disease NOD.c3c4, NOD, and 1803 mice were comparable . However, the HLC composition changed in NOD.c3c4 mice compared with disease-free 1803 mice and young NOD mice . NOD.c3c4 mice developed an increased number of granulocytes and a decrease in the CD4/CD8 ratio from 5 in pre-disease mice to 2 after 30 wk of age .

What Are The Symptoms And Complications Of Autoimmune Hepatitis

Efficacy of Obeticholic Acid in Patients With Primary Biliary Cirrhosis…

Often, the symptoms of autoimmune hepatitis are minor. When symptoms do occur, the most common are fatigue, abdominal discomfort, aching joints, itching, jaundice , enlarged liver, nausea and spider angiomas on the skin. Other symptoms may include dark urine, loss of appetite, pale stools and absence of menstruation. More severe complications can include ascites and mental confusion. In 10%-20% of cases, autoimmune hepatitis may present with symptoms like an acute hepatitis.

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Early Involvement Of The Common Bile Duct : A Specific Predictor Of Disease

We obtained an additional clue to the pathogenesis of ABD by the surprising discovery in young NOD.c3c4 mice of involvement of the CBD illustrated by comparison of the caliber of the CBD and portal vein. The ratio is â¼1:1 in normal mice but considerably greater in NOD.c3c4 mice . This unique dilation of the CBD was found in very young mice. 70% of NOD.c3c4 had CBD dilation at 3 wk of age, a pathology never seen in NOD, B6.G7, 1803, or any other mouse that did not develop ABD. We examined 40 NOD.c3c4 mice aged 24 wk and less. 18 out of 24 female and 11 out of 16 male mice in this age range demonstrated CBDD. To determine whether this finding had predictive power for disease, we examined 20 NOD.c3c4 mice aged > 30 wk and 16 had CBDD. Histologically, there was a 100% correlation for all 16 mice between CBDD and histological evidence of ABD, suggesting that the extrahepatic bile duct lesion is an essential component in the autoimmune process. Histological examination of the CBD confirmed pathological involvement, and, exclusively, NOD.c3c4 mice demonstrated thickening of the wall of the CBD, tortuous dilation, and a substantial subepithelial lymphocytic infiltrate . Notably, anti-CD3 treatment prevented these changes .

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