1. Biliary obstruction, autoimmune diseases of the liver
John J O’Leary

2. Learning objectives
Understand bile duct obstruction [causes and effects]
Understand what is meant by the term auto-immune liver disease:
Primary biliary cirrhosis [PBC]
Primary sclerosing cholangitis [PSC]
Autoimmune hepatitis [AIH]

3. Biliary obstruction

4. Pathological effects of biliary obstruction
High local concentration of bile salts
Inflammation
Fibrosis & scarring Biliary fistula

5. Biliary stasis Liver atrophy Repeated cholangitis Biliary cirrhosis
Fibrosis and scarring
Biliary stasis Liver atrophy
Repeated cholangitis Biliary cirrhosis
& portal HTN
(very late)

6. Causes of Benign strictures

8. Causes of Malignant strictures

9. Symptoms and history: Biliary colic Obstructive jaundice
Cholangitis – Charcot’s triad
jaundice; fever, usually with rigors; and right upper quadrant abdominal pain.
– Reynold’s pentad
+ hypotension and an altered mental state
Past history of cholecystectomy/ other GI surgery (eventful)
History s/o pancreatitis, trauma, radiation, alcohol abuse

10. Signs: Icterus s/o hepatocellular failure Courvoisier's sign
e/o biliary fistula, peritonitis, biloma
Nutritional deficiencies
pale stools
dark urine
itchiness (pruritus)

11. HISTOPATHOLOGY
Under a microscope, the individual hepatocytes will have a brownish-green stippled appearance within the cytoplasm, representing bile that cannot get out of the cell.
Canalicular bile plugs between individual hepatocytes or within bile ducts may also be seen, representing bile that has been excreted from the hepatocytes but cannot go any further due to the obstruction.
When these plugs occur within the bile duct, sufficient pressure (caused by bile accumulation) can cause them to rupture, spilling bile into the surrounding tissue, causing hepatic necrosis. These areas are known as bile lakes, and are typically seen only with extra-hepatic obstruction.

14. Strasberg classification of biliary injury & stricture

15. Laboratory investigations
Bilirubin
Alkaline phosphatase & GGT PT
Anemia, amylase & lipase, ESR, LDH
Tumor markers: CA 19-9, CEA, AFP

16. Imaging studies: Ultrasound CT scan MRCP HIDA scan ERCP
Endoscopic ultrasound
PTC
Fistulography

17. Ultrasonography: Detects intra/extra hepatic ductal dilatation
Less accuracy in defining etiology
Sensitivity – 94% if bilirubin > 10mg%
– 47% otherwise

18. Endoscopic ultrasound:
Extra hepatic bile duct readily visualized
Detects choledocholithiasis (>95%)
Sensitive in diagnosis & staging of malignancy

19. CT Scan: Highly sensitive (esp. with contrast)
Detects site & cause of obstruction
Better anatomical delineation
CT cholangiography

20. MRI & MRCP: Bile – high signal intensity on T2 weighted images
Visualises – biliary dilatation (97-100%), site of obstruction (87%), hepatic parenchyma & vasculature
Only diagnostic

21. HIDA Scan [Hepatobiliary Imino-Diacetic Acid scan]
Helps in diagnosing biliary leaks
Provides functional assessment of incomplete strictures and surgical anastomosis
suggest complete biliary obstruction if the small intestine is not visualized in 60 minutes
insensitive for helping detect biliary dilatation or the site and cause of bile duct obstruction

22. Cholangiography: Gold standard Endoscopic/ percutaneous Features:
define the anatomy of the proximal biliary tree
decompression of the biliary system
Non-operative dilation of bile duct strictures
allow for the simultaneous placement of drainage catheters
of assistance with regard to surgical reconstruction

24. Treatment:
Options:
Endoscopic or percutaneous balloon dilatation and insertion of an endoprosthesis
Surgery
Pre-procedure antibiotic prophylaxis

25. RX of malignant strictures:
Depends on: resectability & stage
general condition
Resectable (15-20%)
– Radical resection with biliary enteric anastomosis
Palliative
– endoscopic stenting
– percutaneous transhepatic stenting
Palliative resection with surgical bypass (mortality – 33%)

26. RX of benign strictures:
Operative management
to surgically re-establish bile flow within the biliary tree and into the proximal gastrointestinal tract in a manner that prevents cholestasis, cholangitis, sludge and stone formation, restricture, or biliary cirrhosis
Non–operative management
to correct the increased resistance to biliary flow caused by a reduction in the diameter of the lumen

29. Autoimmune diseases of the liver

30. Autoimmune liver disease
Primary biliary cirrhosis
Primary sclerosing cholangitis
Autoimmune hepatitis

31. Primary biliary cirrhosis

32. PRIMARY BILIARY CIRRHOSIS
Primary biliary cirrhosis is an autoimmune disease of the liver marked by:
the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver.
when these ducts are damaged, bile builds up in the liver (cholestasis) and over time damages the tissue.
this can lead to scarring, fibrosis and cirrhosis.
it was previously thought to be a rare disease, but more recent studies have shown that it may affect up to 1 in 3-4,000 people; the sex ratio is at least 9:1 (women to men)

33. In some areas of the US and UK the prevalence is estimated to be as high as 1 in This is much more common than in South America or Africa, which may be due to better recognition in the US and UK.
First-degree relatives may have as much as a 500 times increase in prevalence, but there is debate if this risk is greater in the same generation relatives or the one that follows.
After liver transplant, the recurrence rate may be as high as 18% at 5 years, and up to 30% at 10 years. There is no consensus on risk factors for recurrence of the disease

34. The following signs may be present in PBC:
Fatigue
Pruritus (itchy skin)
Jaundice (yellowing of the eyes and skin)
Xanthelasmata (focal collections of cholesterol in the skin, especially around the eyes)
Complications of cirrhosis and portal hypertension:
Fluid retention in the abdomen (ascites)
Hypersplenism
Esophageal varices
Hepatic encephalopathy, up to coma, in extreme cases.
Association with extra-hepatic autoimmune disorder[s] such as Rheumatoid arthritis or Sjögren's syndrome (up to 80% incidence).

35. To diagnose PBC, distinctions should be established from other conditions with similar symptoms, such as autoimmune hepatitis or primary sclerosing cholangitis (PSC).
Diagnostic blood tests include:
Abnormal liver function tests (high alkaline phosphatase, elevated AST, ALT)
Presence of certain antibodies: antimitochondrial antibody, antinuclear antibody (the M2-IgG antimitochondrial antibody is the most specific test)
Abdominal ultrasound or a CT scan is usually performed to rule out blockage to the bile ducts. Previously most suspected sufferers underwent a liver biopsy, and - if uncertainty remained - endoscopic retrograde cholangiopancreatography (ERCP, an endoscopic investigation of the bile duct). Now most patients are diagnosed without invasive investigation since the combination of anti-mitochondrial antibodies (see below) and typical (cholestatic) liver function tests are considered diagnostic. However, a liver biopsy is necessary to determine the stage of disease.
Anti-nuclear antibodies appear to be prognostic agents in PBC. Anti-glycoprotein-210 antibodies, and to a lessor degree anti-p62 antibodies correlate with progression toward end stage liver failure. Anti-centromere antibodies correlate with developing portal hypertension. Anti-np62 and anti-sp100 are also found in association with PBC.

36. STAGES OF DISEASE
Stage 1 - Portal Stage: Normal sized triads; portal inflammation, subtle bile duct damage Granulomas are often detected in this stage.
Stage 2 - Periportal Stage: Enlarged triads; periportal fibrosis and/or inflammation. Typically characterized by the finding of a proliferation of small bile ducts.
Stage 3 - Septal Stage: Active and/or passive fibrous septa.
Stage 4 - Biliary Cirrhosis: Nodules present; garland or jigsaw pattern.

37. The cause of the disease is unknown at this time
an immunological basis for the disease, making it an autoimmune disorder.
most patients (>90%) have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in mitochondria.
an increase in GGT could indicate presence of Primary Biliary Cirrhosis.
57% of patients with acute liver failure have anti-transglutaminase antibodies suggesting a role of gluten sensitivity in primary biliary cirrhosis, and primary biliary cirrhosis is considerably more common in gluten sensitive enteropathy than the normal population.
in some cases of disease protein expression may cause an immune tolerance failure, as might be the case with gp210 and p62, nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients.
Both proteins appear to be prognostic of liver failure relative to anti-mitochondrial antibodies.

38. Course and cure of the disease:
no known cure, but medication may slow the progression
ursodeoxycholic acid (Ursodiol) is the most frequently used treatment. This helps reduce the cholestasis and improves blood test results (liver function tests).
to relieve itching caused by bile acids in circulation, which would normally be removed by the liver, cholestyramine (a bile acid sequestrant) may be prescribed to absorb bile acids in the gut and be eliminated, rather than re-enter the blood stream.
alcoholic beverages are contraindicated.
in advanced cases, a liver transplant, if successful, results in a favourable prognosis.
multivitamins (esp. Vitamin D) and calcium are also recommended as patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K.

40. Contrast-enhanced helical CT image obtained through liver during hepatic arterial phase shows several small, homogeneously enhancing lesions (arrows). Multiple lesions were seen throughout remainder of liver as well.

41. Primary sclerosing cholangitis

42. Primary sclerosing cholangitis (PSC) is a chronic liver disease caused by progressive inflammation and scarring of the bile ducts of the liver.
The inflammation impedes the flow of bile to the gut, which can ultimately lead to liver cirrhosis and liver failure.
The underlying cause of the inflammation is believed to be autoimmunity.
The definitive treatment is liver transplantation.

43. The cause(s) for PSC are unknown.
It is often considered to be an autoimmune disorder.
PSC is associated with inflammatory bowel disease and particularly ulcerative colitis, which coexists in approximately 70% of patients.
Conversely, the prevalence of PSC in ulcerative colitis patients is ~4%.
There is a 2:1 male-to-female predilection of PSC.
There is an increased prevalence of HLA alleles A1, B8, and DR3 in PSC.

44. The disease normally starts from age 30 to 60, though may begin in childhood.
PSC progresses slowly, so the disease can be active for a long time before it is noticed or diagnosed.

45. Signs and symptoms
Fatigue
Severe jaundice with intense itching
Malabsorption (especially of fat) and steatorrhea, leading to decreased levels of the fat-soluble vitamins, A, D, E and K.
Signs of cirrhosis
Ascending cholangitis, or infection of the bile duct.
Pale stools due to biliary obstruction
Dark urine due to excess conjugated bilirubin, which is water soluble, being excreted by the kidneys

46. Diagnosis:
- imaging of the bile duct [ERCP],
- magnetic resonance cholangio-pancreatography (MRCP),
- approximately 80% of patients have perinuclear antineutrophil cytoplasmic antibodies, also called p-ANCA, however this finding is not specific for PSC.
- antinuclear antibodies and anti-smooth muscle antibodies are found in 20%-50% of PSC patients and, likewise, are not specific for the disease.
- full blood count, liver enzymes, bilirubin levels (usually grossly elevated), renal function, electrolytes.
faecal fat determination is occasionally ordered when the symptoms of malabsorption are prominent.
The differential diagnosis can include: primary biliary cirrhosis, drug induced cholestasis, cholangiocarcinoma, and HIV-associated cholangiopathy.

47. Treatment:
ursodiol, a bile acid naturally produced by the liver, which has been shown to lower elevated liver enzyme numbers in people with PSC, but has not yet been proven effective at prolonging the life of the liver.
medication to relieve itching (antipruritics) and bile acid sequestrants (cholestyramine), antibiotics to treat infections, and vitamin supplements, as people with PSC are often deficient in vitamin A, vitamin D, vitamin E and vitamin K.
in some cases, ERCP, which may involve stenting of the common bile duct, may be necessary in order to open major blockages (dominant strictures).
- Liver transplantation is the only proven long-term treatment of PSC. Indications for transplantation include recurrent bacterial cholangitis, jaundice refractory to medical and endoscopic treatment, decompensated cirrhosis and complications of portal hypertension.

48. PSC is associated with cholangiocarcinoma

52. Primary sclerosing cholangitis
Primary sclerosing cholangitis. Single-shot fast spin-echo MRCP image shows multifocal strictures and dilatations of the intrahepatic bile ducts

53. Autoimmune hepatitis

54. Overview Definition Prevalence Clinical manifestations Pathogenesis
Subtypes
Diagnosis
Prognostic indices
Treatment

55. Autoimmune Hepatitis self-perpetuating hepatocellular inflammation
unknown cause
characterization:
histologic features of interface hepatitis
hypergammaglobulinemia
serum autoantibodies
affects all ages, may be asymptomatic, frequently has an acute onset, and can also present as fulminant hepatitis.
Autoimmune hepatitis has an incidence of 1-2 per 100,000 per year, and a prevalence of 10-20/100,000. As with most other autoimmune diseases, it affects women much more often than men (70%).

56. Prevalence
Mean annual incidence among white northern Europeans: 1.9 cases per 100,000 per year
US: 100, ,000 people
W>M 3.6:1, unexplained.
all ages, ethnic groups.
Frequency of AIH among pts with chronic liver disease in North America is 11-23%
Accounts for 5.9% in the National Institutes of Health Liver transplantation database.
Prevalence of AIH is greatest among northern European white groups who have a high frequency of HLA-DR3 and HLA-DR4
Why women:
Greater HLA DR4 alleles than men
Hi Estrogen favor TH2 response
Low or normal Estrogen favors TH1 response
AIH improves in pregnancy b/c of hi Estrogen

57. Clinical manifestations
Cholestatic features may be present, but they don’t dominate the clinical picture.
Most common symptom: Fatigability
Most common physical finding: Hepatomegaly 78%
Pruritus is mild. Actually, intense pruritus or wt loss argues against AIH.
Other stigmata of liver dz
Concurrent immunologic diseases are common and involve diverse organ systems, most frequently the thyroid.
Laboratory wise, predominance in AST elevation,
Elevated globulins are polyclonal, but IgG fraction predominates
Hyperbilirubinemia
Immunologic markers are key findings and we’ll return to these later.

58. Pathogenesis Unknown mechanism
Most popular hypotheses:interactive factors:
Triggering agent
A genetic predisposition
various determinants of autoantigen display
immunocyte activation
effector cell expansion.
The most popular hypotheses evoke a constellation of interactive factors that include:

59. Pathogenesis Triggering agents infectious agents, drugs, toxins.
Multiple agents suggest that triggering epitope is a short amino acid sequence that is common in many antigens.
Possible long lag time b/w exposure to the trigger and onset of the disease
Triggering factor may not be needed for perpetuation of the disorder.

60. Pathogenesis Loss of self-tolerance –
molecular mimicry of a foreign antigen
self antigen
Only the cytochrome monooxygenase P-450 IID6 (CYP2D6) has been recognized as an autoantigen.
multiple self-antigens or foreign antigens may satisfy the minimal structural requirements and serve as immunogenic peptides
Most common explanation for the loss of self tolerance is:
Molecular mimicry of a foreign antigen, that is there immune response to a foreign antigen that is structurally similar to an endogenous substance.
Self antigen or “autoantigen” which means there’s a tissue constituent that evokes an immune response.

61. Pathogenesis genetic predisposition
Susceptibility HLA allelles encoding MHC class II:
influences the presentation of these autoantigens to CD4+ helper T cell thereby initiating an immune response.
the initiation of the immune response is dependent on the antigen binding groove of the class II MHC molecule. The sequence of amino acids that make up this antigen binding groove is encoded by a person’s HLA alleles. Thus, there are specific alleles that make a person more susceptible to developing AIH by influencing the immune response, and in turn the clinical manifestations and behavior of AIH.
Autoimmune promoters:
polymorphisms for TNF-α gene and cytotoxic T lymphocyte antigen 4 gene have been associated with increased immune reactivity and disease severity of AIH type I
Other: Vitamin D receptor (VDR) gene, point mutation of the tyrosine phosphatase CD45 gene, polymorphisms of the Fas gene, MHC class 1 chain-related A gene.
A person’s genetic predisposition is important b/c it directly influences the presentation of these antigens to CD4 helper T cell thereby initiating an immune response.
And this seen in Susceptibility HLA alleles, and autoimmune promoters
Recalling from immunology, the initiation of the immune response is dependent on the antigen binding groove of the class II MHC molecule. The sequence of amino acids that make up this antigen binding groove is encoded by a person’s HLA alleles. Thus, there are specific alleles makes a person susceptible to developing AIH by influencing the immune response, and in turn the clinical manifestations and behavior of AIH.
Autoimmune proomoters found inside and outside of the MHC may affect the occurrence of AIH either in synergy with susceptibility alleles or in lieu of them.
-polymorphisms for TNF-α gene and cytotoxic T lymphocyte antigen 4 gene have been associated with increased immune reactivity and disease severity of AIH type I
-Other genetic promoters: Vitamin D receptor (VDR) gene, point mutation of the tyrosine phosphatase CD45 gene, polymorphisms of the Fas gene, MHC class 1 chain-related A gene.
Extra notes:
MHC molecules are polymorphic and polygenic due to the consideration of vast number of antigens that are available.
MHC I detects self
MHC II detects foreign

62. APC CD4 T Cell MHC Class II CD4 Peptide Antigen Cytokines TCR
APC internalizes an antigen and processes it as an antigenic peptide, and presents it to a CD4 T helper cell, which is the principal effector cell. It’s activation and differentiation are the initial steps in the pathogenic pathway. It is the interaction of the antigenic peptide with the amino acids of the antigen binding groove of the MHC class II molecule that is important in triggering an immunogenic response.
CD4 T Cell

63. Pathogenesis
Mechanism of Liver cell destruction via cellular and humoral mechanisms
Cell-mediated cytotoxicity
TH1 response (IL-2, IFN-γ, TNF-α)  clonal expansion of cytotoxic T lymphocytes that infiltrate and destroy hepatocytes.
Genetic polymorphism that affects TNF- production may facilitate this pathway.
Antibody-dependent cell-mediated cytotoxicity
TH2 response (IL-4,5,6,8,10,13)  B cell stimulation  Ab production immunocyte complexes on hepatocyte surface  targeted by NKT cells
Anti-inflammatory effects that counters TH1 action
Combination of mechanisms
Predominant mechanism depends on the phenotypic differentiation of CD4+ helper T cell, which in turn reflects the cytokine milieu, which in itself reflects the polymorphisms of the cytokine genes that favor excessive production of some modulators, such as TNF-, or deficient in others.
The NKT (natural killer T) cells are abundant in the liver
Produce interferon-gamma and TNF-alpha
Target cells with aberrant MHC expression, virally infected cells, cancer cells

64. AIH subtypes AIH type 1 AIH type 2 AIH type 3
on the basis of immunoserologic markers.
The International Autoimmune Hepatitis Group has not endorsed this subclassification.
Used mainly for descriptive value

65. AIH type 1 Most common form worldwide
characterized by the presence or absence of SMA and/or ANA in serum
Surrogate markers: Peri-nuclear anti-neutrophil cytoplasmic antibodies which occur in PSC and chronic UC, are found in 90% of patients who have type 1 AIH.
Bimodal age distribution (10-20; 45-70)
Female:male 3.6:1
Risk factors for type 1 AIH
in whites of northern European descent [HLA-DR3 (DRB1*0301)] and –DR4 (DRB1*0401)]

66. AIH type 1 Associated with concurrent extra-hepatic diseases
Autoimmune thyroiditis (12%)
Graves disease (6%)
Chronic UC (6%) * (cholangiography to exclude PSC)
<1% RA, pernicious anemia, systemic sclerosis, Coomb’s test-positive HA, ITP, symptomatic cryoglobulinemia, leukocytoclastic vasculitis, nephritis, erythema nodosum, SLE, fibrosing alveolitis.
40% of AIH type 1 presents with an acute onset of symptoms/signs indistinguishable from that of acute viral or toxic hepatitis and the disease may appear fulminant in fashion.
target autoantigen is unknown, but ASGPR (asialoglycoprotein receptor) found on hepatocyte surface is a candidate
Responds well to glucocorticoids

67. AIH type 2
Characterized by presence of anti-LKM1 (liver/kidney microsome type 1) in serum
P-ANCA is not found
Mainly children (2-14 yo) but also seen in adults (in Europe, 20% of pts are adults; in US, 4% of pts are >18 yrs)
Only AIH with an identified target autoantigen: cytochrome monooxygenase P-450 IID6 (CYP2D6) found in the cytosol of hepatocytes.
Recognized homologies b/w epitopes of CYP2D6 and genome of HCV.
<10% of Europeans with chronic Hep C have detectable anti-LKM1
Suggests molecular mimicry and antibody cross-reactivity, multiple exposures to virus mimicking self may be a way to break self-tolerance and induce AIH type 2.
Anti-LKM1 + pts with chronic Hep C in US pts is rare – differences in indigenous virus or host susceptiblity?
Acute or fulminant presentation is possible
Thus essential to screen all pts who have an acute decompensation for type-specific autoantibodies.
Associated with HLQA-B14, -DR3, -C4A-QD
Susceptibility factor in German and Brazilians: DRB1*07
Like AIH type 1, also responds well to glucocorticoids

68. AIH type 2 Distinct form of anti-LKM positive AIH
Occurs in association with autoimmune polyendocrinopathy disorder (APECED) aka Polyglandular autoimmune syndrome type I (APS1)
rare autosomal recessive disorder
Caused by a signal gene mutation of the APS1 gene which encodes a transcription factor, autoimmune regulator (AIRE) which is expressed in epithelial and dendritic cells within the thymus where it regulates clonal deletion of autoreactive T cells, thus can affect self tolerance
Features of this disease are ectodermal dystrophy, mucocutaneous candidiasis, multiple endocrine gland failure (parathyroids, adrenals, ovaries)
Marked by the presence of numerous organ and non-organ specific autoantibodies and multiple concurrent autoimmune diseases.
most common among Finns, Sardinians, and Iranian Jews
Pts with APECED and AIH have an aggressive liver disease that does not respond well to standard immunosuppressive regimens.

69. AIH type 3 Least established form of the disease
Designation largely abandoned
Characterized by presence of antibodies to soluble liver antigen and liver/pancreas (anti-SLA, anti- LP)
30-50 yo
Target autoantigens: thought to be Glutathione S-transferase, but a transfer ribonucleoprotein (tRNP) 50-kd protein was described in 2000 as the more likely target.
Clinical and laboratory features that are indistinguishable from AIH type 1
Also responds well to glucocorticoids

70. AIH subtypes

71. Variant forms
These pts have autoimmune features but do not satisfy the criteria for a definite or probable dx of AIH.
Overlap syndrome: Typically have manifestations of AIH and another type of chronic liver disease
AIH + PBC: Have AIH plus antimitochondrial antibodies plus histologic findings of cholangitis
Behavior of the disease and response to treatment depend mainly on the component of the disease that predominates.
AIH + PSC: Need cholangiography if they have:
Lymphocytic, pleomorphic, fibrous cholangitis on histologic examination
Cholestatic lab findings
Concurrent IBD
Fail to respond to glucocorticosteroids
The absence of cholangiographic changes doesn’t preclude the dx of PSC, b/c small duct disease may be present.
Autoimmune cholangitis: characterized by Chronic hepatocellular inflammation that has features of AIH and AMA-negative PBC or small duct PSC. They have normal cholangiogram.
They have variable response to prednisone and ursodeoxycholic acid.
Cryptogenic Chronic Hepatitis:
Considered to be a outlier syndrome, that is they have findings that are incompatible with dx of AIH by current dx criteria (which we’ll define in a minute)
theory is that it’s a form of AIH that has escaped detection by conventional immunoserologic assays.
b/c of lack of autoantibodies, they are sometimes excluded inappropriately from glucocorticoid treatment,
But both autoantibody +/- pts respond well to glucocorticosteroid treatment

72. Diagnosis Determination of serum aminotransferase and –globulin levels
Rule out ddx
Detection of ANA and /or SMA, or in their absence, anti-LKM1
Liver tissue examination

73. Diagnosis determination of serum aminotransferase and –globulin levels
Predominant serum aminotransferase abnormality
Hypergammaglobulinemia
exclusion of other chronic liver diseases that have similar features
hereditary causes: (Wilson disease, alpha1-antitrypsin deficiency, genetic hemochromatosis
infectious causes: chronic viral hepatitis A, B, C
drug-induced liver disease (ETOH, minocycline, nitrofurantoin, INH, propylthiouracil, methyldopa)
NASH
immune cholangiopathies of PBC, PSC, autoimmune cholangitis

74. Diagnosis Detection of ANA and /or SMA, or in their absence, anti-LKM1
conventional immunoserologic tests for AIH:
antinuclear antibodies (ANA),
present alone (13%), along with SMA (54%)
also be found in PBC, PSC, chronic viral hepatitis, drug-related hepatitis, NASH, alcohol-induced liver disease
smooth muscle antibodies (SMA),
Directed against actin and nonactin components (tubulin, vimentin, desmin, skeletin)
present (87%), sole marker (33%), with ANA (54%)
antibodies to liver/kidney microsome type 1 (anti-LKM1)
Typically occurs in absence of SMA and ANA
rare in the US (4% of adults with AIH in US)
perinuclear anti-neutrophil cytoplasmic antibodies (pANCAs) are common in type 1 AIH,
useful in evaluation patients who lack conventional autoantibodies.
Used to reclassify patients with cryptogenic chronic hepatitis as AIH, but they have not been formally assimilated into the diagnostic algorithm
Do not have diagnostic specificity nor do they have prognostic implications.

75. Diagnosis Detection of ANA and /or SMA, or in their absence, anti-LKM1
NEW antibodies:
investigational in nature, but sufficient promise to support a probable diagnosis, not generally available, assays are not standardized
actin (anti-actin)
has less sensitivity, but greater specificity than SMA for AIH type 1
asialoglycoprotein receptor (anti-ASGPR)
transmembrane glycoprotein on the hepatocyte surface which can capture, internalize, display potential antigens
Seen in AIH type 1
soluble liver antigen/liver-pancreas (A)
Seen in AIH type 3
used to reclassification of patients with cryptogenic chronic hepatitis as AIH
liver cytosol type 1 (anti-LC1)
Have been proposed as an antigenic target.
Seen in AIH type 2
Prevalence is higher in pts < 20, Rare in pts >40

76. Diagnosis Liver tissue examination
Liver bx is essential to establish diagnosis and assess disease severity to determine need for treatment
histological features of interface hepatitis (hallmark of the syndrome)
portal plasma cell infiltration typifies the disorder
lack of portal plasma cell infiltration does not preclude dx
1999 update: lobular hepatitis is now part of histologic spectrum
aminotransferase and gamma-globulin levels do not predict histologic pattern of injury or the presence or absence of cirrhosis.
Histologic changes, such as ductopenia or destructive cholangitis, may indicate a variant syndrome of AIH and PSC, AIH an PBC, or autoimmune cholangitis.
Findings of steatosis or iron overload may suggest alternative diagnoses:
NASH
Wilson disease
Chronic Hep C
Drug toxicity
genetic hemochromatosis

77. Interface hepatitis
Interface hepatitis. Here you can see the limiting plate of the portal tract, demarcating the hepatocyte boundary, is disrupted by a lymphoplasmacytic infiltrate. This histologic pattern is the hallmark of autoimmune hepatitis, but it is not disease specific.
Hematoxylin and eosin, *200.
Extra notes:
Acute onset AIH pattern: panancinar hepatitis that resembles an acute viral or drug-induced hepatitis.
Centrilobular or pervenular (rappaprot zone 3) hepaitits that resembles an acute toxic injury.
Here you can see the limiting plate of the portal tract, demarcating the hepatocyte boundary, is disrupted by a lymphoplasmacytic infiltrate.
This histological pattern is the hallmark of autoimmune hepatitis, but it is not disease specific.

78. Plasma cell infiltration
Plasma cells are identified by their eccentric, clock-face nucleus, and pale perinuclear cytoplasm. There are not pathognomonic of the disease nor required for diagnosis.

79. Lobular Hepatitis
Figure 75–2. Lobular hepatitis in which mononuclear inflammatory cells line the sinusoidal spaces. Typically, lobular hepatitis coexists with interface hepatitis, but it may be pronounced during acute onset or during relapse after treatment withdrawal. Hematoxylin and eosin, *200.

80. PBC
Marked mononuclear cell infiltrate surrounding and destroying a bile duct in primary biliary cirrhosis
Marked mononuclear cell infiltrate surrounding and destroying
a bile duct in primary biliary cirrhosis

81. PSC
Mononuclear cell infiltration and characteristic concenctric fibrosis around a small bile duct in PSC
Mononuclear cell infiltration and characteristic concentric fibrosis around a small bile duct in PSC

82. Diagnostic Criteria Definite dx:
Exclusion of other chronic liver diseases of hereditary, infectious, or toxic etiologies
laboratory findings indicating substantial immunoreactivity
Liver bx shows interface hepatitis and no histological changes suggestive of other diseases as we had mentioned.
Probable dx:
Is Justified when findings are compatible with AIH but insufficient for a definite dx.
Patients who lack conventional autoantibodies can have probable dx if they are seropositive for antibodies to asialoglycoprotein receptor (anti-ASGPR), soluble liver antigen/liver-pancreas (anti-SLA/LP), actin (anti-actin), or liver cytosol type 1 (anti-LC1).

83. Scoring System
Because of diverse manifestations of AIH and if the dx is unclear, the International Autoimmune Hepatitis Group (IAHG) Scoring Criteria produced an objective scoring method which grades clinical, laboratory, histological features and gives a composite score derived before and after corticosteroid tx.
Quantifies the dx, helps with objective comparison b/w patient populations, accommodates pts with atypical features.
Useful as an investigational tool in clinical trials. rarely necessary in clinical practice
It’s not a diagnostic index used to discriminate b/w classical syndromes of chronic liver dz.
Extra notes:
Definite diagnosis prior to corticosteroid tx requires a score greater than 15, whereas the definite diagnosis after corticosteroid tx requires a score greater than 17
Sensitivity

84. Prognosis
Prognosis of AIH relates mainly to the severity of liver inflammation as reflected in
the lab indices and histologic findings.
Sustained serum aminotransaminases levels of more than 10 fold normal or more than 5 fold normal with serum globulin concentrations at least twofold normal identifies pts with early mortality.
Each pattern of liver cell injury has its own prognostic implications
HLA status influences treatment outcome
But presently, clinical applications of HLA testing in AIH are uncertain, and determinations are not routinely made

85. Prognosis 40% develop with cirrhosis
54% develop esophageal varices w/in 2 years
20% die from variceal hemorrhage if they don’t receive any treatment
hepatocellular carcinoma can occur in this pts but risk is small.
Presence of ascites or hepatic encephalopathy identifies pts with a poor prognosis.
13-20% of patients can have spontaneous resolution regardless of disease activity.
A critical determinant of survival in the untreated patient is early tolerance of the disease.
Of pts who survive the early, most active stage of the disease, inactive cirrhosis develops in 41% of pts.
Untreated patients who have initial severe disease and survive the first 2 years of illness typically survive long term

86. Treatment
-Two treatment regimens are comparable and effective: Prednisone only and combination therapy
-Preferred treatment: Azathioprine with prednisone is preferred to prednisone alone b/c the combination produces fewer glucocorticoid –related side effects (10% versus 44%)
After starting dose of Pred, taper it down to maintenance dose

87. Indication for liver transplantation
Pts’ with ascites and hepatic encephalopathy identifies pt’s with poor prognosis. They can still respond to glucocorticoid therapy and should be treated before a decision regarding liver transplantation is made.
Indicated in decompensated pt with hepatic encephalopathy, ascites, and/or variceal hemorrhage during therapy for treatment failure.
Effective in pts who deteriorate during or after corticosteroid tx.
After transplantation, the autoantibodies and hypergammaglobulinemia disappear within 2 years the 5 year survival rate is 96%. Actuarial 10 year survival 75%.
Recurrent disease after transplantation is common but has been described mainly in patients who have inadequate immunosuppression.
RARE cases (3-5%) pts can develop AIH de novo after undergoing transplantation for non-autoimmune liver disease. Immunosuppression with CyA is a common feature. TX with prednisone or azathioprine is effective.
Mech? Promiscuous Lymphocytes by excessive exposure to antigens?; impaired autoreactive cells by Cya?

88. AIH Summary
self-perpetuating hepatocellular inflammation of unknown cause
Genetic predispostion
Diverse clinical features
3 subtypes AIH and variants
Dx:
interface hepatitis
hypergammaglobulinemia
serum autoantibodies
Rule out other liver diseases
Consider in all pts with acute & chronic liver diseases and those with allograft dysfunction after transplantation
Prednisone, Azathioprine
Evolving treatment options