en ENGLISH
eISSN: 2084-9834
ISSN: 0034-6233
Reumatologia/Rheumatology
Bieżący numer Archiwum Artykuły zaakceptowane O czasopiśmie Suplementy Rada naukowa Recenzenci Bazy indeksacyjne Prenumerata Kontakt Zasady publikacji prac
NOWOŚĆ
Portal dla reumatologów!
www.ereumatologia.pl
SCImago Journal & Country Rank


 
5/2020
vol. 58
 
Poleć ten artykuł:
Udostępnij:
więcej
 
 
Artykuł przeglądowy

Liver involvement in rheumatic diseases

Joanna Podgórska
1
,
Paulina Werel
1
,
Jakub Klapaczyński
1
,
Dorota Orzechowska
1
,
Mariusz Wudarski
2
,
Andrzej Gietka
1

1.
Department of Internal Diseases and Hepatology, Central Clinical Hospital of Ministry of the Interior and Administration, Warsaw, Poland
2.
Systemic Connective Tissue Diseases Clinic and Polyclinic, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
Reumatologia 2020; 58, 5: 289–296
Data publikacji online: 2020/10/13
Plik artykułu:
- Liver involvement.pdf  [0.10 MB]
Pobierz cytowanie
ENW
EndNote
BIB
JabRef, Mendeley
RIS
Papers, Reference Manager, RefWorks, Zotero
AMA
APA
Chicago
Harvard
MLA
Vancouver
 
 

Introduction

The autoimmune connective tissue diseases (CTD) have a complex pathogenesis with a multifactorial etiology. In the course of CTD develop an autoimmune response leading to chronic inflammation and that sometimes may cause multiorgan dysfunction.

The liver is a life-sustaining organ which is responsible for detoxification of drugs and other harmful substances, metabolism of hormones, storage and release of proteins, cholesterol and vitamins and also an active organ of immune response.

The liver abnormalities are not included in connective tissue diseases’ diagnostic criteria, except adult onset Still’s disease (AOSD), in which elevated aminotransferases are subsumed in minor criteria according to the Yamaguchi et al. [1] criteria. For this reason, AOSD will not be discussed in our article.

Liver dysfunction occurs in 43% of patients with connective tissue disorders [2]. In some cases (27–37%) further investigation does not reveal other than rheumatological causes, the biochemical abnormalities are mild or transient and no progressive and clinically relevant changes are found in liver biopsy [2, 3].

The diverse course of the autoimmune rheumatic diseases ranges from asymptomatic elevation of transaminases or cholestatic enzymes, jaundice, hepatomegaly, to hepatic cirrhosis or even to acute liver failure. In the histology of liver biopsy, there are no specific features of connective tissue disease and the most frequent findings are: hepatic steatosis, chronic hepatitis, regenerative nodular hyperplasia, hepatic fibrosis, cirrhosis, granulomas, cholangitis, destruction of biliary canaliculus and vasculitis [4, 5].

This article reviews various aspects of liver involvement only in the most common, immunologically mediated rheumatic diseases, which typically have multisystem involvement (Table I).

Table I

Rheumatic diseases and reported coexisting liver diseases

Rheumatic diseasesSigns, liver test abnormalitiesReported coexisting liver diseases
Systemic lupus erythematosusArthralgia, jaundice, hepatomegaly, splenomegaly, presence of ANA, ALT and AST elevationDrug side effects
NAFLD, NRHL, AIH, PBC Non-specific reactive changes
Anti-phospholipid syndromeAbdominal pain, ascites, hepatomegalyBudd-Chiari syndrome NRHL
Rheumatoid arthritisCholestasis, GGT elevationNAFLD, unspecific histological findings, PBC, AIH, NRHL
Felty’s syndromeSplenomegaly, portal hypertension, esophageal variceal bleedingNRHL
Primary Sjögren’s syndromeCholestasis, ALT, AST elevation, splenomegaly, portal hypertension, esophageal variceal bleedingPBC, PSC, AIH, NRHL
Systemic sclerosisCholestasisPBC
Idiopathic inflammatory myopathiesAST > ALT, CK elevation, cholestasisPBC
Systemic vasculitides: polyarteritis nodosa, Behçet’s diseaseHepatomegaly, jaundice, cholestasis, abdominal pain, ascites, hepatomegalyHepatitis B, Budd-Chiari syndrome

[i] ANA – anti-nuclear antibodies, ALT – alanine aminotransferase, AST – aspartate aminotransferase, GGT – γ-glutamyl transferase, CK – creatine kinase, NAFLD – nonalcoholic fatty liver disease, NRHL – nodular regenerative hyperplasia of the liver, AIH – autoimmune hepatitis, PBC – primary biliary cholangitis, PSC – primary sclerosing cholangitis

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease of unknown etiology. It affects mostly women in reproductive age. In the pathophysiology, defects in the apoptosis play the main role. This leads to chronic inflammation in various tissues and organs.

The connection between SLE and hepatitis was noticed in the 1950s and it was described as a lupoid hepatitis by Cowling et al. [6] in 1954. Lupoid hepatitis turned out to be one of the variants of autoimmune hepatitis (AIH) which affects young women and manifests with SLE-like symptoms such as arthralgia or arthritis, fever, loss of appetite, weakness, presence of anti-nuclear antibodies (ANA) or lupus anticoagulant and hypergammaglobulinemia.

Nevertheless, AIH and SLE are two different diseases, rarely cooccurring with each other, despite common symptoms such as arthralgia, hypergammaglobulinemia and ANA [7, 8].

However, liver dysfunction is observed in 59.7% of the patients affected by SLE. It can have multiple causes and it can be associated with exacerbation of the disease (28.5%), the drugs side effects (30.9%) or coexistence of the primary hepatic disease (fatty liver disease in 20%, AIH in 4.9%, primary biliary cholangitis (PBC) in 2.4%, cholangitis in 1.6%, alcohol in 1.6% or viral hepatitis in 0.8%) [9].

Moreover, it is worth remembering that jaundice can be the effect of hemolytic anemia in SLE. In the differential diagnosis, AIH and SLE-associated hepatitis must be considered. The serological marker dsDNA antibody is specific for SLE, but it can be also detected in AIH [10].

On the other hand, the antibodies specific for AIH such as soluble liver antigen antibodies (anti-SLA), liver-kidney microsomal antibodies (anti-LKM) or anti- smooth muscle antibodies (anti-SMA) are rarely present in SLE [10, 11].

Liver biopsy is crucial because of characteristic histological findings in AIH (listed in Table II) while hepatitis accompanying SLE is histologically unspecific [11, 12]. It is important to make the proper diagnosis because of differences in the natural history and treatment.

Table II

Comparison of systemic lupus erythematosus (SLE)-associated hepatitis and autoimmune hepatitis

ParametersSLE-associated hepatitisAutoimmune hepatitis (AIH)
SymptomsArthralgia or arthritis, fever, loss of appetite, weaknessAsymptomatic (35%), weakness, mild right upper quadrant pain, nausea, jaundice, arthralgia, rarely rash or fever
ANAMost patients80% in type 1 AIH
Lupus anticoagulantPresentAbsent
ds-DNAPresentMay be present (up to 57%)
Anti-SMARarely presentUsually present in type 1 AIH
Anti-LKMAbsentPresent in type 2 AIH
Anti-SLAAbsentPresent in type 3 AIH
Histological findingsHistologically unspecific: lobular infiltrates with paucity of lymphocytes, mild chronic inflammationInterface hepatitis, lymphocytic infiltrates in portal tracts and extending into the lobule, emperipolesis (active penetration by one cell into and through a larger cell) and hepatic rosette formation
ProgressionBenignCan lead to cirrhosis
PrognosisGood10-year survival rate without treatment of AIH is < 27%

[i] ANA – anti-nuclear antibodies, anti-SMA – anti-smooth muscle antibodies, anti-LKM – liver-kidney microsomal antibodies, anti-SLA – soluble liver antigen antibodies

The SLE-associated hepatitis does not need to be treated with corticosteroids and its natural history does not lead to cirrhosis, whereas the prognosis in untreated AIH is highly disadvantageous. The 10-year survival rate without treatment of AIH is less than 27%, and when treated it is approximately from 83.8 to 94% [1315].

In prospective studies, liver biopsy performed in patients with SLE and elevated liver enzymes showed most frequently nonalcoholic fatty liver disease (NAFLD) (20–73%), vasculitis (21%), nodular regenerative hyperplasia of the liver (NRHL) (5.7%), chronic hepatitis (2.4%), cirrhosis (1.1%) or fibrosis (0.8%) [16].

Anti-phospholipid syndrome

Anti-phospholipid syndrome was described by Hughes et al. [17, 18] in 1986. It is marked by arterial or venous thrombosis, miscarriages, thrombocytopenia and presence of antiphospholipid antibodies (APL) (such as lupus anticoagulant, anticardiolipin or b2-glycoprotein) [19].

Antiphospholipid antibodies can be found in many autoimmunological or neoplastic diseases and infections. However, it can also be identified accidentally in 2–5% of the healthy population and its prevalence rate increases with age [20].

The most frequent abdominal manifestation of APS is thrombosis of hepatic vessels, from main hepatic arteries or veins to small hepatic vessels. Hepatic vein thrombosis, also named Budd-Chiari syndrome, is caused by occlusion of the hepatic veins and it presents with a classical triad of abdominal pain, ascites and hepatomegaly. It can be the first manifestation of APS [21].

Interestingly, APL probably also play a role in pathophysiology of NRHL [22].

Rheumatoid arthritis and Felty’s syndrome

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease with unknown etiology that primarily affects joints, leading to their destruction, but other organs can also be involved (lungs, heart, kidneys and hemopoietic system). The liver is rarely affected, but abnormalities in liver tests can be detected in 5 to 77% of patients with RA [23].

Cholestasis is most commonly observed and it correlates with the activity of RA. Moreover, Lowe et al. [24] discovered a correlation between level of g-glutamyl transferase and erythrocyte sedimentation rate.

Histological abnormalities in liver biopsy were found in 74% of patients with RA. 43% of the patients presented with unspecific findings such as mild inflammatory infiltrations in portal tracts or minor focal necrosis of hepatocytes, 22% were diagnosed with NAFLD and 11% with fibrosis, but only 1.1% of them were diagnosed with cirrhosis [25].

Felty’s syndrome (FS) was described in 1924 and it is a variant of seropositive RA with splenomegaly and neutropenia. It develops in 1% of patients with long-lasting RA and is characterized by severe destructive changes in joints and higher prevalence of rheumatoid nodules, lymphadenopathy, vasculopathy, leg ulcers and infections in comparison with typical RA [26].

Moreover, higher prevalence of NRHL was noted in patients with FS, contrary to cirrhosis, which is rarely diagnosed. Nodular regenerative hyperplasia of the liver can cause portal hypertension and in consequence esophageal variceal bleeding [27].

On the other hand, as opposed to hepatic cirrhosis, such patients do not suffer from encephalopathy. In patients diagnosed with FS and NRHL, screening gastroscopy should be considered in search of esophageal varices. Variceal band ligation can be used as the primary prevention and transjugular intrahepatic portosystemic shunt (TIPS) as the secondary prevention of variceal bleeding [28].

The splenectomy also may be beneficial in the treatment of portal hypertension [29].

Primary Sjögren’s syndrome

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune inflammatory disease that causes lymphocytic infiltrations in exocrine glands, which results in secretion impairment and inflammation in different organs. The characteristic symptoms such as mucous membrane dryness appear in the advanced stage. The diagnosis should be made according to ACR-EULAR classification criteria from 2016 that are based on the weighed sum of 5 items.

The histopathological findings (focal lymphocytic sialadenitis) and the presence of anti-SSA/Ro antibodies are the most typical for pSS. Also, it is essential to exclude a history of head and neck radiotherapy, hepatitis C virus infection, sarcoidosis, amyloidosis, IgG4-related disease and graft vs. host reaction [30].

Other antibodies that can be detected in pSS are anti-SSB/La, rheumatoid factor, and antinuclear antibodies. Nevertheless, they are not specific and are not included in the classification criteria [31].

Not only exocrine glands, but also other organs such as lungs, thyroid, kidneys, pancreas and liver can be affected in pSS. Diverse liver symptoms are observed in 27 to 49% of cases, depending on research [32]. Liver disorders associated with pSS are PBC, AIH, primary sclerosing cholangitis and NRHL [33].

The most common are PBC and AIH, which total more than 50% [34]. Primary biliary cholangitis is a chronic non-infectious cholangitis with undefined etiology that causes destruction of the intrahepatic bile ducts. It is a rare condition that more often affects women, but it is also the most frequently occurring autoimmune liver disorder.

The serologic marker specific to PBC are anti-mitochondrial antibodies that occur in 90–95% of patients. In a multicenter study, AMA were present in 22% of pSS cases, 17% of SLE, 10% of RA and 8% of scleroderma sera [35].

It is worth emphasizing that pSS and PBC have many common features. In both disorders the inflammatory process begins in bile or gland duct epithelium, and is characterized by impaired surface expression of HLA class 2. There are inflammatory infiltrations with CD4 lymphocyte dominance [36].

The coexistence of PBC in pSS is estimated at around 6%. Biopsies from patients with pSS and AMA revealed findings characteristic for PBC in 92% [37]. The asymptomatic patients with AMA should be monitored for development of PBC. It is very important to diagnose PBC at an early stage and start proper treatment with ursodeoxycholic acid [38].

Systemic sclerosis

Systemic sclerosis (SSc) is a chronic systemic connective tissue disease which presents with progressive fibrosis of skin and internal organs and also injuries of small arteries (vasculopathy).

There are two types of SSc depending on the extent of skin involvement. Limited systemic sclerosis affects skin areas distal to elbows and knees. By contrast, diffuse systemic sclerosis affects skin of the proximal parts of the limbs and torso [39].

The frequency of SSc is higher in middle-aged female patients. Despite rare incidence of the disease, it poses a great social problem associated with progression of disability, high costs of treatment and increased mortality due to organ damage (mainly lung involvement). The most common liver disease accompanying SSc is PBC.

It occurs in 3–17% of patients and may account for more than 50% of liver diseases associated with SSc [40, 41]. Moreover, AMA, specific for PBC, are detected in more than 25% of patients with SSc.

As well as anticentromere antibodies (ACA), which are characteristic for lSSc, were found in more than 30% of patients with PBC and 80% of patients with the overlap syndrome PBC/SSc [41, 42].

Screening for presence of ACA seems to be a reasonable option in patients with PBC, and if positive, capillaroscopy should be performed. If giant capillaries are found, further diagnostic evaluation of SSc should be completed.

In addition, patients with lSSc should be evaluated for AMA presence, and if positive, the observation of cholestasis is recommended.

Idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies are a heterogenic group of muscle diseases with diverse symptoms and etiology. The main classes of IIMs are polymyositis (PM), dermatomyositis and inclusion body myositis.

They can occur as a primary muscle disease or be associated with other systemic connective tissue disorders such as mixed connective tissue disease or as an overlap syndrome with Sjögren’s disease, SSc, SLE or RA.

The high activity of muscle enzymes such as creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), aldolase and lactate dehydrogenase (LDH) is a marker of muscle cell degeneration or cell membrane damage. Elevated transaminases can be mistakenly interpreted as liver dysfunction. In clinical practice, the AST to ALT ratio should be assessed, and if the result is > 1, the CK test may be crucial in differential diagnosis.

Also myoglobin level may be helpful in assessment of the level of muscle damage and its concentration correlates with activity of the disease. Liver diseases are very rare in inflammatory myopathies. Only a few cases of PBC were described in patients with inflammatory myopathy [43].

Systemic vasculitides

Systemic vasculitides are a heterogenous group of diseases which are characterized by inflammation of blood vessel walls that causes narrowing and occlusion of the vessels. Consequently, this leads to episodes of ischemic changes and necrosis of tissues and organs supplied by these vessels.

Systemic vasculitides can be divided into three major groups based on the size of vessel affected (large, medium or small vessels) according to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. All types of vasculitides can affect the gastrointestinal system [44].

Polyarteritis nodosa (PAN) is necrotizing inflammation of medium and small vessels that causes organ damage in the gastrointestinal system in more than 50% of cases. The liver can also be affected in the course of PAN and it can manifest as hepatomegaly, jaundice, cholestasis without jaundice and even as massive hepatic necrosis. There are two subsets of PAN: primary of unknown etiology and secondary associated with presence of hepatitis B virus (HBV-related PAN).

The approach to treatment of PAN depends on the presence of hepatitis B virus (HBV). Conventional therapy of PAN relies on corticosteroids and additionally on cyclophosphamide in more severe cases. In HBV-related PAN, it is important to start treatment with antiviral agents, plasmapheresis and prednisone 60 mg/per day decreased to zero at the end of the second week.

Prolonged use of steroids or immunosuppressive therapy in HBV-infected patients increase the risk of hepatitis flare-up and may lead to fulminant liver disease [45]. Due to worldwide vaccinations against HBV and common screening, the rate of HBV in PAN has decreased from 30% to 8% [46].

Intrahepatic vessel inflammation can also be present in Takayasu’s arteritis, temporal arteritis and granulomatosis with polyangiitis.

Budd-Chiari syndrome is the most common and most serious manifestation of liver disease in Behçet’s disease (BD). Patients with BD should be screened for Budd-Chiari syndrome with duplex ultrasonography [47].

Hepatotoxicity of drugs used in rheumatology

Drug-induced liver injury (DILI) is the main reason for drugs’ withdrawal from clinical trials or even from market registered substances. It may occur as a direct result of a drug or its metabolites toxicity affecting hepatocytes (intrinsic DILI) or through immune activation (idiosyncratic DILI).

Intrinsic DILI is predictable (occurs in a large proportion of exposed individuals), dose related and occurs within hours or days (Table III).

Table III

Hepatotoxicity of drugs used in rheumatology

DrugsHepatotoxic effectOutcome
NSAIDsHepatocellular or cholestatic patternLiver damage, reversible after discontinuation of the suspected NSAIDs
MethotrexateNAFLDLiver fibrosis and cirrhosis (BMI, alcohol consumption and lack of folic acid supplementation may play a role)
LeflunomideElevated liver enzymesLiver tests normalize during ongoing treatment
Tumor necrosis factor inhibitorsAIH, cholestasis, jaundice, acute liver failure (very rare) hepatitis B reactivationSome patients require treatment of AIH (glucocorticoids) and discontinuation of anti-TNF-treatment
TocilizumabElevated liver enzymes (transient)Liver tests normalize during ongoing treatment or after dose reduction
JAK inhibitorsElevated ALT (transient)Liver tests normalize during ongoing treatment

[i] NSAIDs – nonsteroidal anti-inflammatory drugs, NAFLD – nonalcoholic fatty liver disease, AIH – autoimmune hepatitis, ALT – alanine aminotransferase, BMI – body mass index

A typical example of intrinsic DILI is acetaminophen. Idiosyncrasy is an unexpected side effect of the drug, independent of dose, time and route of administration, and it demonstrates variable latency to onset (from days to weeks). It is associated with congenital or acquired enzymopathy. The pathogenesis of liver damage in idiosyncrasy has not been elucidated.

Nonsteroidal anti-inflammatory drugs

Typical examples of an idiosyncratic reaction and liver damage are nonsteroidal anti-inflammatory drugs (NSAIDs) and clavulanic acid.

Nonsteroidal anti-inflammatory drugs are the most widely used medications in the world. Since benoxaprofen was recalled in 1982 because of cases of fatal jaundice and renal failure, liver damage due to NSAIDs has been found as a class effect [48].

From 5 to 15% of patients using NSAIDs develop elevated liver enzymes but the liver damage is mild and reversible after drug discontinuation. In view of cross-reactivity among the same class of NSAIDS, re-administration of NSAIDs should be avoided [49].

Methotrexate

Methotrexate (MTX) belongs to a class of drugs known as antimetabolites and is commonly used in the treatment of many autoimmune diseases such as RA, psoriasis, psoriatic arthritis, juvenile idiopathic arthritis, spondyloarthropathies, SLE, polymyalgia rheumatica, and PM.

The United States Food and Drug Administration (FDA) approved MTX as a therapy for RA in 1988. It has become the standard of care and the first-line therapy for patients with RA. In patients who have an incomplete response to MTX, it could be administered in combination with either a biological agent or other antirheumatic drugs. Methotrexate has a relatively good safety profile.

The most common side effect is gastrointestinal intolerance such as nausea, stomatitis or diarrhea. Prolonged MTX therapy may increase the risk of hepatotoxicity leading to fatty liver disease, fibrosis and cirrhosis. Factors such as body mass index (BMI), alcohol consumption, concomitant medications such as NSAIDs, and lack of folic acid supplementation may additionally contribute to transaminase elevation. Toxicity of MTX is related to a cumulative dose and the application frequency (daily administration is more harmful than once per week application) [50].

According to an international group of experts’ guidelines, the blood count, liver enzymes and creatinine level are recommended to be monitored on a monthly basis for at least 6 months and then every 3 months. If the increase in aminotransferases (AST or ALT) > 3 × upper limit of normal (ULN) is confirmed, the administration of MTX should be discontinued. If liver test abnormalities persist, liver biopsy ought to be performed. In case of normalization of aminotransferases, MTX may be reinstituted at a lower dose [51].

Also, routine liver biopsy after a cumulative dose of 1, 3 and 8 γ can be considered, but guidelines from different societies vary on this issue. When the liver biopsy reveals significant or severe fibrosis or cirrhosis, discontinuation of MTX is highly recommended [52].

Leflunomide

Leflunomide (LEF) acts by inhibiting pyrimidine’s intracellular pathways and preventing lymphocyte proliferation and differentiation. It is registered and regularly prescribed as the first-line treatment for use in patients with psoriatic arthritis and RA.

Common adverse effects for patients receiving leflunomide treatment include gastrointestinal complaints, skin rash and reversible alopecia. ALT/AST elevations > 2 × ULN occurred in 1–2% of patients on MTX or LEF monotherapy compared with 5% with the combination of both of them [53].

Tumor necrosis factor inhibitors

Tumor necrosis factor inhibitors (TNFi) are biological agents that were introduced as rheumatological treatment in the 1990s. Biological disease-modifying antirheumatic drugs (bDMARDs) act against cytokines and inflammatory cells in RA and inhibit the immunological response. A common side effect connected with this mechanism is activation of the opportunistic infections tuberculosis and HBV [54].

For this reason, the European Association for the Study of the Liver (EASL) recommends preventive use of nucleoside analogues by non-active carriers of Hbs antigen during and 12 months after the biological treatment [55].

On the other hand, in patients with chronic hepatitis C, the anti-TNF therapy seems to be safe and does not provoke an increase of liver enzymes or the viral load [56]. Tumor necrosis factor inhibitors may also rarely cause cholestasis, jaundice, AIH or acute liver failure [57, 58].

Tocilizumab

Tocilizumab (TCZ) is a humanized, monoclonal antibody against the interleukin-6 receptor and has been successfully developed as a therapeutic agent for treatment of RA, systemic onset juvenile idiopathic arthritis and in many other autoimmune conditions.

Tocilizumab is effective in the improvement of systemic inflammatory symptoms such as anemia and fatigue. Additionally, it improves sleep quality, inhibits serum amyloid A protein production and eliminates amyloid deposition in amyloid A amyloidosis.

The clinically significant adverse events that may occur with TCZ treatment include infections, abnormalities in lipid and liver function tests and gastrointestinal side effects. Tocilizumab treatment can be associated with elevation of liver enzymes, but most of them are transient and occur within 12 months of TCZ initiation and resolve after lowering the dose of tocilizumab/disease-modifying antirheumatic drugs [59].

Janus kinase inhibitors

Janus kinase (JAK) inhibitors are a new class of drugs – oral targeted synthetic DMARDs, added recently to second line treatment of RA, which inhibit components of the intracellular inflammatory JAK signaling cascade.

The first JAK inhibitors are tofacitinib and baricitinib and were approved in 2017 by the European Medicines Agency (EMA) for treatment of patients with moderate to severe RA and an inadequate response to prior disease-modifying antirheumatic drugs. Tofacitinib is also helpful in treatment of ulcerative colitis and psoriasis. Long-term extension studies have shown that tofacitinib demonstrated a stable safety profile.

The most common adverse events are infections (nasopharyngitis, upper respiratory tract infections, herpes zoster), bone marrow suppression (neutropenia, lymphocytopenia and decrease in platelet count) and hyperlipidemia. Only 1.2% of patients confirmed increased ALT levels > 3 × ULN, but most of them subsided spontaneously without discontinuation of the study drug [60].

Conclusions

Abnormalities in liver function tests are very common in patients with rheumatic diseases. Most frequently, non-specific and transient elevation of the liver function tests is associated with activity of connective tissue disease and does not require any special intervention.

On the other hand, if the abnormal liver function tests (cholestasis or elevated aminotransferases) persist independently of the activity of rheumatic disease, further hepatological investigations should be carried out and primary autoimmune liver diseases, viral hepatitis and drug hepatotoxicity must be excluded.

Notes

[4] Conflicts of interest The authors declare no conflict of interest.

References

1 

Yamaguchi M, Ohta A, Tsunematsu T, et al. , authors. Preliminary criteria for classification of adult Still’s disease. J Rheumatol. 1992. 19:p. 424–430

2 

Kojima H, Uemura M, Sakurai S, et al. , authors. Clinical features of liver disturbance in rheumatoid diseases: clinicopathological study with special reference to the cause of liver disturbance. J Gastroenterol. 2002. 37:p. 617–625. DOI: 10.1007/s005350200098

3 

Matsumoto T, Kobayashi S, Shimizu H, et al. , authors. The liver in collagen diseases: pathologic study of 160 cases with particular reference to hepatic arteritis, primary biliary cirrhosis, autoimmune hepatitis and nodular regenerative hyperplasia of the liver. Liver. 2000. 20:p. 366–373. DOI: 10.1034/j.1600-0676.2000.020005366.x

4 

Youssef WI, Tavill AS , authors. Connective tissue diseases and the liver. J Clin Gastroenterol. 2002. 35:p. 345–349. DOI: 10.1097/00004836-200210000-00012

5 

Abraham S, Begum S, Isenberg D , authors. Hepatic manifestations of autoimmune rheumatic diseases. Ann Rheum Dis. 2004. 63:p. 123–129. DOI: 10.1136/ard.2002.001826

6 

Cowling DC, Mackay IR, Taft LI , authors. Lupoid hepatitis. Lancet. 1956. 271:p. 1323–1326. DOI: 10.1016/s0140-6736(56)91483-0

7 

Aringer M, Costenbader K, Daikh D, et al. , authors. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol. 2019. 71:p. 1400–1412. DOI: 10.1002/art.40930

8 

Alvarez F, Berg PA, Bianchi FB, et al. , authors. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999. 31:p. 929–938. DOI: 10.1016/s0168-8278(99)80297-9

9 

Takahashi A, Abe K, Saito R, et al. , authors. Liver dysfunction in patients with systemic lupus erythematosus. Intern Med. 2013. 52:p. 1461–1465. DOI: 10.2169/internalmedicine.52.9458

10 

Czaja AJ, Morshed SA, Parveen S, Nishioka M , authors. Antibodies to single-stranded and double-stranded DNA in antinuclear antibody-positive type 1-autoimmune hepatitis. Hepatology. 1997. 26:p. 567–572. DOI: 10.1002/hep.510260306

11 

Lohse AW, Mieli-Vergani G , authors. Autoimmune hepatitis. J Hepatol. 2011. 55:p. 171–182. DOI: 10.1016/j.jhep.2010.12.012

12 

Hennes EM, Zeniya M, Czaja AJ, et al. , authors. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008. 48:p. 169–176. DOI: 10.1002/hep.22322

13 

Kirk AP, Jain S, Pocock S, et al. , authors. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut. 1980. 21:p. 78–83. DOI: 10.1136/gut.21.1.78

14 

Feld JJ, Dinh H, Arenovich T, et al. , authors. Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome. Hepatology. 2005. 42:p. 53–62. DOI: 10.1002/hep.20732

15 

Roberts SK, Therneau TM, Czaja AJ , authors. Prognosis of histological cirrhosis in type 1 autoimmune hepatitis. Gastroenterology. 1996. 110:p. 848–857. DOI: 10.1053/gast.1996.v110.pm8608895

16 

Chowdhary VR, Crowson CS, Poterucha JJ, Moder KG , authors. Liver involvement in systemic lupus erythematosus: case review of 40 patients. J Rheumatol. 2008. 35:p. 2159–2164. DOI: 10.3899/jrheum.080336

17 

Hughes G, Harris EN, Gharavi A , authors. The anticardiolipin syndrome. J Rheumatol. 1986. 13:p. 486–489

18 

Hughes GR , author. The antiphospholipid syndrome: ten years on. Lancet (London, England). 1993. 342:p. 341–344. DOI: 10.1016/0140-6736(93)91477-4

19 

Miyakis S, Lockshin MD, Atsumi T, et al. , authors. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006. 4:p. 295–306. DOI: 10.1111/j.1538-7836.2006.01753.x

20 

Petri M , author. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun. 2000. 15:p. 145–151. DOI: 10.1006/jaut.2000.0409

21 

Uthman I, Khamashta M , authors. The abdominal manifestations of the antiphospholipid syndrome. Rheumatology (Oxford). 2007. 46:p. 1641–1647. DOI: 10.1093/rheumatology/kem158

22 

Perez-Ruiz F, Zea-Mendoza AC , authors. Nodular regenerative hyperplasia of the liver and antiphospholipid antibodies. J Clin Gastroenterol. 1998. 27:p. 90–91. DOI: 10.1097/00004836-199807000-00021

23 

Schlenker Ch, Halterman T, Kowdley KV , authors. Rheumatologic disease and the liver. Clin in Liver Dis. 2011. 15:p. 153–164. DOI: 10.1016/j.cld.2010.09.006

24 

Lowe JR, Pickup ME, Dixon JS, et al. , authors. Gamma glutamyl transpeptidase levels in arthritis: a correlation with clinical and laboratory indices of disease activity. Ann Rheum Dis. 1978. 37:p. 428–431. DOI: 10.1136/ard.37.5.428

25 

Mills PR, MacSween RN, Dick WC, et al. , authors. Liver disease in rheumatoid arthritis. Scott Med J. 1980. 25:p. 18–22. DOI: 10.1177/003693308002500104

26 

Balint GP, Balint PV , authors. Felty’s syndrome. Best Pract Res Clin Rheumatol. 2004. 18:p. 631–645. DOI: 10.1016/j.berh.2004.05.002

27 

Blendis LM, Lovell D, Barnes CG, et al. , authors. Oesophageal variceal bleeding in Felty’s syndrome associated with nodular regenerative hyperplasia. Ann Rheum Dis. 1978. 37:p. 183–186. DOI: 10.1136/ard.37.2.183

28 

Bosch J , author. Salvage transjugular intrahepatic portosystemic shunt: is it really life-saving? J. Hepatol. 2001. 35:p. 658–660. DOI: 10.1016/s0168-8278(01)00238-0

29 

Stock H, Kadry Z, Smith JP , authors. Surgical management of portal hypertension in Felty’s syndrome: a case report and literature review. J Hepatol. 2009. 50:p. 831–835. DOI: 10.1016/j.jhep.2008.10.035

30 

Shiboski CH, Shiboski SC, Seror R, et al. , authors. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol. 2017. 69:p. 35–45. DOI: 10.1002/art.39859

31 

Garcia-Carrasco M, Ramos-Casals M, Rosas J, et al. , authors. Primary Sjogren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine (Baltimore). 2002. 81:p. 270–280. DOI: 10.1097/00005792-200207000-00003

32 

Kaplan MJ, Ike RW , authors. The liver is a common non-exocrine target in primary Sjögren’s syndrome. A retrospective review BMC Gastroenterol. 2002. 2:p. 21DOI: 10.1186/1471-230x-2-21

33 

Montańo-Loza AJ, Crispín-Acuńa JC, Remes-Troche JM, et al. , authors. Abnormal hepatic biochemistries and clinical liver disease in patients with primary Sjögren’s syndrom. Ann Hepatol. 2007. 6:p. 150–155

34 

De Santis M, Crotti C, Selmi C , authors. Liver abnormalities in connective tissue diseases. Best Pract Res Clin Gastroenterol. 2013. 27:p. 543–551. DOI: 10.1016/j.bpg.2013.06.016

35 

Zurgil N, Bakimer R, Moutsopoulos HM, et al. , authors. Antimitochondrial (pyruvate dehydrogenase) autoantibodies in autoimmune rheumatic diseases. J Clin Immunol. 1992. 12:p. 201–209

36 

Selmi C, Meroni PL, Gershwin ME , authors. Primary biliary cirrhosis and Sjögren’s syndrome: Autoimmune epithelitis. J Autoimmun. 2012. 39:p. 34–42. DOI: 10.1016/j.jaut.2011.11.005

37 

Skopouli FN, Barbatis C, Moutsopoulos HM , authors. Liver involvement in primary Sjogren’s syndrome. Br J Rheumatol. 1994. 33:p. 745–748. DOI: 10.1093/rheumatology/33.8.745

38 

EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol. 2009. 51:p. 237–267. DOI: 10.1016/j.jhep.2009.04.009

39 

Hudson M, Fritzler MJ , authors. Diagnostic criteria of systemic sclerosis. J Autoimmun. 2014. 48-49:p. 38–41. DOI: 10.1016/j.jaut.2013.11.004

40 

Rigamonti C, Shand LM, Feudjo M, et al. , authors. Clinical features and prognosis of primary biliary cirrhosis associated with systemic sclerosis. Gut. 2006. 55:p. 388–394. DOI: 10.1136/gut.2005.075002

41 

Rigamonti C, Bogdanos DP, Mytilinaiou MG, et al. , authors. Primary biliary cirrhosis associated with systemic sclerosis: diagnostic and clinical challenges. Int J Rheumatol. 2011. 2011:p. 976427DOI: 10.1155/2011/976427

42 

Liberal R, Grant CR, Sakkas L, et al. , authors. Diagnostic and clinical significance of anti-centromere antibodies in primary biliary cirrhosis. Clin Res Hepatol Gastroenterol. 2013. 37:p. 572–585. DOI: 10.1016/j.clinre.2013.04.005

43 

Jariwala S, Tomann T, Burger A , authors. Primary biliary cirrhosis associated with inflammatory myopathy in a 57 Year Old Male. Clinical Immunology. 2008. 127:p. S109–S110. DOI: 10.1016/j.clim.2008.03.310

44 

Jennette JC, Falk RJ, Bacon PA, et al. , authors. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013. 65:p. 1–11. DOI: 10.1002/art.37715

45 

Guillevin L, Mahr A, Cohen P, et al. , authors. French Vasculitis Study Group, Short-term corticosteroids then lamivudine and plasma exchanges to treat hepatitis B virus-related polyarteritis nodosa. Arthritis Rheum. 2004. 51:p. 482–487. DOI: 10.1002/art.20401

46 

Guillevin L, Lhote F, Cohen P, et al. , authors. Polyarteritis nodosa related to hepatitis B virus. A prospective study with long-term observation of 41 patients. Medicine (Baltimore). 1995. 74:p. 238–253. DOI: 10.1097/00005792-199509000-00002

47 

Bayraktar Y, Balkanci F, Bayraktar M, Calguneri M , authors. Budd-Chiari syndrome: a common complication of Behçet’s disease. Am J Gastroenterol. 1997. 92:p. 858–862

48 

Dahl SL, Ward JR , authors. Pharmacology, clinical efficacy, and adverse effects of the nonsteroidal anti-inflammatory agent benoxaprofen. Pharmacotherapy. 1982. 2:p. 354–366. DOI: 10.1002/j.1875-9114.1982.tb03212.x

49 

Burt AD, Portmann BC, Ferrell LD , editors; Lewis JH, Kleiner DE , editors. Hepatic injury due to drugs, herbal compounds, chemicals and toxins. In: MacSween’s Pathology of the Liver. 2012. 6th. Edinburgh: Churchill Livingstone Elsevier; p. 645–760

50 

Visser K, van der Heijde DM , authors. Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature. Clin Exp Rheumatol. 2009. 27:p. 1017–1025

51 

Visser K, Katchamart W, Loza E, et al. , authors. Multinational evidence- based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 2009. 68:p. 1086–1093. DOI: 10.1136/ard.2008.094474

52 

Kremer JM, Alarcón GS, Lightfoot RW Jr, et al. , authors. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. Arthritis Rheum. 1994. 37:p. 316–328. DOI: 10.1002/art.1780370304

53 

Curtis JR, Beukelman T, Onofrei A, et al. , authors. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis. 2010. 69:p. 43–47. DOI: 10.1136/ard.2008.101378

54 

Ostuni P, Botsios C, Punzi L, et al. , authors. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis. 2003. 62:p. 686–687. DOI: 10.1136/ard.62.7.686

55 

European Association for the Study of the Liver , author. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017. 67:p. 370–98. DOI: 10.1016/j.jhep.2017.03.021

56 

Ferri C, Ferraccioli G, Ferrari D, et al. , authors. Safety of anti-tumor necrosis factor-α therapy in patients with rheumatoid arthritis and chronic hepatitis C virus infection. J Rheumatol. 2008. 35:p. 1944–1949

57 

Tobon GJ, Cańas C, Jaller JJ, et al. , authors. Serious liver disease induced by infliximab. Clin Rheumatol. 2007. 26:p. 578–581. DOI: 10.1007/s10067-005-0169-y

58 

Ghabril M, Bonkovsky HL, Kum C, et al. , authors. Liver injury from tumor necrosis factor- antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol. 2013. 11:p. 558–564. DOI: 10.1016/j.cgh.2012.12.025

59 

Genovese MC, Kremer JM, van Vollenhoven RF, et al. , authors. Transaminase levels and hepatic events during tocilizumab treatment: pooled analysis of long-term clinical trial safety data in rheumatoid arthritis. Arthritis Rheumatol. 2017. 69:p. 1751–1761. DOI: 10.1002/art.40176

60 

Wollenhaupt J, Silverfield J, Lee EB, et al. , authors. Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014. 41:p. 837–852. DOI: 10.3899/jrheum.130683

Copyright: © 2020 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
 
facebook linkedin twitter
© 2022 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.