Non-classical phenotypes of autoimmune hepatitis and advances in diagnosis and treatment

Table 1 Non-classical phenotypes of autoimmune hepatitis

Non-classical phenotype	Salient features
Acute severe disease	Corticosteroids effective in 36%-100%[49]
	Protracted treatment can be complicated by infection[49]
	High mortality if no better within 2 wk of therapy[85]
	MELD score ≥ 12 identifies 97% of treatment failures[58]
Asymptomatic mild hepatitis	Common (25%-34%) but unstable state[202122878889]
	Symptoms develop in 26%-70%[2021]
	Progression possible if untreated[20212287]
	Improves quickly with therapy[22]
Atypical histological features	Centrilobular necrosis is an early acute form[18333435363792]
	Transition to interface hepatitis possible[35]
	Coincidental biliary changes lack cholestatic profile[41]
	Fatty changes may co-exist[5894]
Absent or variant serological markers	Seronegativity possible in 13%[31]
	Other features and treatment outcome similar[3132100]
	Non-standard autoantibodies possible[101102103104]
	Conventional autoantibodies may be expressed later[30]
	Screen for celiac disease[105106107108]
Concurrent cholangiographic changes	Abnormal cholangiograms in 44% with CUC[116]
	Poor outcome if biliary changes and CUC[121122123124]
	MRC abnormalities in 8% adults without CUC[117]
	MRC abnormalities may be associated with fibrosis[119]
Male gender	0.2-0.5 cases/100 000 per year[127128]
	Low frequency of concurrent immune diseases[130131132]
	No diversity of HLA DRB1*04 alleles[130131132]
	Better survival than women[136]
Non-Caucasian	Cholestatic features may be common[45141142143]
	Male predominance possible[47]
	Socioeconomic factors important[137138146147]

MELD: Model of End Stage Liver Disease; MRC: Magnetic resonance cholangiography; CUC: Chronic ulcerative colitis; HLA: Human leukocyte antigen.

Table 2 Revised original pre-treatment scoring system[10]

Variable	Result	Points	Variable	Result	Points
Gender	Female	+2	HLA	DR3 or DR4	+1
AP:AST (or ALT) ratio	> 3	-2	Immune disease	Thyroiditis, colitis, others	+2
	< 1.5	+2
γ-globulin or IgG level above normal	> 2.0	+3	Other markers	Anti-SLA, actin, LC1, pANCA	+2
	1.5-2.0	+2
	1.0-1.5	+1
	< 1.0	0
ANA, SMA, or anti-LKM1 titers	> 1:80	+3	Histological features	Interface hepatitis	+3
	1:80	+2		Plasmacytic	+1
	1:40	+1		Rosettes	+1
	< 1:40	0		None of above	-5
				Biliary changes	-3
				Other features	-3
AMA	Positive	-4	Treatment response	Complete	+2
				Relapse	+3
Viral markers	Positive	-3
	Negative	+3
Drugs	Yes	-4	Pretreatment aggregate score
	No	+1	Definite diagnosis		> 15
			Probable diagnosis		10-15
Alcohol	< 25 g/d	+2	Post-treatment aggregate score
	> 60 g/d	-2	Definite diagnosis		> 17
			Probable diagnosis		12-17

AP: AST (or ALT) ratio: Ratio of alkaline phosphatase level to aspartate or alanine aminotransferase level; Anti-SLA: Antibodies to soluble liver antigen; Anti-LC1: Antibodies to liver cytosol type 1; pANCA: Perinuclear anti-neutrophil cytoplasmic antibodies; IgG: Immunoglobulin G; ANA: Antinuclear antibodies; SMA: Smooth muscle antibodies; Anti-LKM1: Antibodies to liver/kidney type 1; AMA: Antimitochondrial antibodies; HLA: Human leukocyte antigen.

Table 3 Simplified scoring system of the International Autoimmune Hepatitis Group[65]

Variable	Result	Points
Autoantibodies
ANA or SMA	≥ 1:40	+1
ANA or SMA	≥ 1:80	+2
Antibodies to liver kidney microsome type 1	≥ 1:40	+2
Antibodies to soluble liver antigen	Positive	+2
Immunoglobulin level
Immunoglobulin G	> UNL	+1
	> 1.1 ULN	+2
Histological findings
Morphological features	Compatible	+1
	Typical	+2
Viral disease
Absence of viral hepatitis	No viral markers	+2
Pretreatment aggregate score
Definite diagnosis		≥ 7
Probable diagnosis		6

ULN: Upper limit of normal.

Table 4 Therapeutic advances in autoimmune hepatitis

Advance	Nature	Attribute
Improved current therapy	Initial therapy until resolution of liver tests and tissue	Prevention of relapse after drug withdrawal[70]
	Long-term azathioprine therapy after relapse or incomplete response	Prevention of disease progression[7173125]
	Pretreatment vaccination for viruses	Protection against morbidity of concurrent viral infection[74]
New drugs	Calcineurin inhibitors (cyclosporine, tacrolimus)	Salvage therapy[150–157]
	Purine antagonists (6-mercaptopurine, mycophenolate)	Salvage therapy[161–166]
	Budesonide (combined with azathioprine)	Effective and safe front line therapy[75]
Potential molecular interventions	Synthetic blocking peptides	Block autoantigen presentation[186187]
	Cytokine manipulations	Promote anti-inflammatory effects[188]
	T cell vaccination	Eliminate cytotoxic liver-infiltrating clone[189]
	Oral tolerance (high or low dose regimen)	Reduce immune response (low dose) or induce anergy (high dose)[190191]
	Mesenchymal stem cells (human bone marrow-derived)	Replace damaged hepatocytes[200]