Challenge of liver disease in systemic lupus erythematosus: Clues for diagnosis and hints for pathogenesis

Table 1 Biochemical and histological liver abnormalities in systemic lupus erythematosus patients according to different reports in the literature

Ref.	Study type	Patientswith SLE	NO. of patients with biochemicalalterations and alteration types	Liver histological findings
Mackay et al[11]	Retrospective	19	(n = 19) ↑ AST, ALT	Minimal changes, portal fibrosis, steatosis, inflammation (n = 11) Normal (n = 6) Chronic hepatitis (n = 2)
Chwalińska-Sadowska et al[12]	Retrospective	18	NA	Minimal changes (n = 13) Normal (n =5)
Runyon et al[13]	Retrospective	238	(n = 124) ↑ AST, ALT, total bilirubin, ALP, GGT, LDH (≥ 2 × ULN)	(n = 33) Steatosis (n = 12) Others: cirrhosis, chronic hepatitis, granulomatosis, chronic hepatitis, steatosis, cholestasis, centrilobular necrosis
Gibson et al[14]	Retrospective	81	(n = 64) ↑ AST, ALT, ALP	(n = 7) Portal inflammation (n = 5) Steatosis (n = 1) Chronic hepatitis (n = 1)
Miller et al[15]	Prospective	260	(n = 84) ↑ AST, ALT, ALP	Minimal changes (n = 14)
Matsumoto et al[17]	Retrospective	73	NA	Hepatic arteritis (n = 11) Steatosis (n = 53) RNH (n = 5) Viral hepatitis (n = 2) SLE-PBC overlap syndrome (n = 1) SLE-AIH overlap syndrome (n = 1)
Luangjaru et al[9]	Retrospective	225	(n = 80) ↑ AST, ALT ( ≤ 4 × ULN)	NA
Chowdhary et al[7]	Retrospective	192	(n = 40) ↑ AST, ALT	HCV (n = 3) Steatosis (n =5) SLE-AIH overlap syndrome (n = 4) SLE-PBC overlap syndrome (n = 3) Cryptogenic cirrhosis (n = 1)
Piga et al[3]	Retrospective	242	(n = 59) ↑ AST, ALT (≥ 2 × ULN)	NA
Her et al[138]	Retrospective	141	(n = 46) ↑ Total bilirubin, AST, ALT, LDH, ALP (≥ 2 × ULN)	NA
Huang et al[90]	Retrospective	1533	(n = 134) ↑ AST, ALT (≥ 2 × ULN during 2 yr)	Chronic Hepatitis (n = 6) Minimal changes (n = 4) Normal (n = 3)
Zheng et al[2]	Retrospective	504	(n = 47) ↑ Total bilirubin (13%), ALT (98%), ALP (42%), GGT (49%)	(n = 10) Portal blood cell infiltration (n = 8) Hydropic degeneration (n = 8) Steatosis (n = 2) Mild cholestasis (n = 2) Focal necrosis (n= 1) Nodular cirrhosis (n = 1)
Takahashi et al[18]	Prospective	206	(n = 123) ↑ AST, ALT (99%) ↑ ALP and GGT (81%)	(n = 25) Lupus hepatitis (n = 16): Unspecific reactive hepatitis (88%) Active hepatitis (12%) SLE-AIH overlap syndrome (n = 6): Interface hepatitis (100%) Cirrhosis (33%) SLE-PBC overlap syndrome (n = 3)

SLE: Systemic lupus erythematosus; ULN: Upper limit of normal; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; LDH: Lacto dehydrogenase; ALP: Alkaline phosphatase; GGT: Gamma glutamil transferase; HCV: Hepatitis C virus; PBC: Primary biliary cirrhosis; AIH: Autoimmune hepatitis.

Table 2 Laboratory abnormalities in the different hepatic manifestations associated with systemic lupus erythematosus

Hepatic alteration	Laboratory abnormalities
Hepatic steatosis	GGT, ALT/AST
Viral hepatitis	ALT, AST, HCV, cryoglobulinemia
Toxic hepatitis	ALP, GGT, AST/ALT, bilirubin
Nodular regenerative hyperplasia	ALT, AST, thrombocytopenia
Primary biliary cirrhosis	ALP, GGT, AMA
Autoimmune hepatitis	ANA, ASMA, gammaglobulin
Hepatic venous thrombosis	Antiphospolipidic antibodies
Lupus hepatitis	Anti-ribosomal P autoantibodies

AMA: Antimitocondrial antibody; ANA: Antinuclear antibody; ASMA: Antismooth muscle antibody; GGT: Gamma glutamil transferase; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

Table 3 Hepatotoxicity induced by drugs used in lupus treatment

Drug	Liver injury and clinical significance
Corticosteroids	Hepatomegalia
	Fatty liver
NSAIDs	Asymptomatic ALT increase
	Hepatocellular, cholestatic, or mixed injury
ASA	Acute and chronic hepatocellular injury
	(resolve with withdrawal)
Methotrexate	Asymptomatic ALT increase at high doses
	Esteatosis, fibrosis, or cirrhosis
Anti-malarial drugs1	Rare hepatotoxic effects
	Porphyria cutanea tarda
Azatioprine	Cholestasis, peliosis, SOS, RNH
Thioguanine	SOS, RNH, portal hypertension
Ciclophosphamide	Rare case reports at conventional doses
	SOS at high doses (resolve with dose reduction)
Mycophenolate mofetil	Asymptomatic ALT increase
	(resolve with dose reduction)
Rituximab	No liver reactions have been reported
Belimumab	No liver reactions have been reported

¹Anti-malarial drugs: chloroquine, hydroxychloroquine. ALT: Alanine aminotransferase; NSAIDs: Non-steroidal antiinflamatory drugs; ASA: Acetylsalicilic acid; RNH: Nodular regenerative hyperplasia; SOS: Sinusoidal obstruction syndrome.