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Systemic Sclerosis and the Liver

2021; Lippincott Williams & Wilkins; Volume: 18; Issue: 2 Linguagem: Inglês

10.1002/cld.1074

2046-2484

Ellen W. Green, Leslie E. Kahl, Janice H. Jou,

Liver Disease Diagnosis and Treatment

Answer questions and earn CME Content available: Author Interview and Audio Recording Systemic sclerosis (SSc) is a heterogenous, multisystem autoimmune disease defined by fibrosis and classified by extent of skin and organ involvement with varying clinical manifestations, progression rates, morbidity, and mortality. This heterogeneity complicates diagnosis, as well as epidemiological estimates. Globally, in areas of higher incidence, such as North America, SSc affects approximately 14 to 21 per million per year.1 Higher rates are seen in middle-aged women, but there is relatively poorer prognosis in men and African Americans.1, 2 To date, there exists a paucity of literature on SSc and liver involvement. SSc is thought to be caused by an environmental insult activating genetic predisposition through epigenetic modifications to initiate a cascade of autoimmune inflammation via both innate and adaptive systems resulting in vascular dysfunction and, ultimately, fibrosis of the skin and internal organs (Fig. 1).1, 3, 4 Numerous gene variants have been implicated in SSc, and first-degree family members exhibit a relative risk ratio of 13 for development.1 However, exact SSc pathogenesis remains unclear. Pathology of the gastrointestinal (GI) lumens is postulated to initiate with neuroimmunological damage through autoantibodies or adrenergic overdrive.5 Autoimmunity, such as through anti-mitochondrial antibodies (AMAs) or PDC-E2, a T cell mitochondrial target, is a common driver of cholangiocyte activation and dysfunction as seen in primary biliary cholangitis (PBC), the most common hepatic pathology in SSc.4, 6 As with other end-organ fibrosis in SSc, it is thought that progressive endothelial dysfunction and microvascular damage result in reduced vascular capacity, causing hypoxic damage to terminal tissues. Both pathological pathways result in cyclic inflammatory crosstalk, including overproduction of a key fibrosis regulator, transforming growth factor-β (TGF-β), resulting in fibrosis and organ dysfunction. Biopsy early in the disease course may appear benign, but ultimately pathological fibrosis can affect the GI tract from mouth to anus, resulting in histopathology demonstrating smooth muscle atrophy and fragmentation. Liver biopsy results mostly relate to PBC and range from intrahepatic bile duct damage to portal inflammation to classic findings of necrosis and immune cell invasion.6, 7 The American College of Rheumatology/European League Against Rheumatism's (ACR/EULAR's) 2013 criteria8 are the cornerstone of SSc diagnosis (Table 1), and the single finding of "skin thickening of the fingers of both hands that extends proximal to the metacarpophalangeal [MCP] joints" is sufficient, but not necessary, with classification based on the extent of skin involvement. No GI findings are included because of lack of specificity, but 1 in 10 patients with SSc present initially with these symptoms, and 90% of patients with SSc eventually experience these complications, which contribute significantly to morbidity and reduced quality of life (Tables 2 and 3). Previously CREST dcSSc Systemic sclerosis sine scleroderma Overlap syndrome Liver disease is a rare complication of SSc, and as such many large studies and registries often do not mention hepatological manifestations of SSc. Smaller studies and cases indicate approximately 1.5% of patients with SSc have chronic liver disease9 and up to 8.8% may have hepatic pathology on autopsy.10 Historically called Reynold's disease for the observation of co-occurrence of SSc and PBC, PBC is now recognized as the most commonly associated hepatic disease, affecting 2% of patients with SSc,11 followed by autoimmune hepatitis (AIH), with rare co-occurrence of AIH-PBC overlap. Rarely have other hepatic pathologies been documented, including isolated cases of primary sclerosing cholangitis, idiopathic noncirrhotic portal hypertension, nodular regenerative hyperplasia, infarction as a result of vasospasm, and vasculitis. In PBC—identified by the triad of elevated alkaline phosphatase, IgM, and AMA—at least half of patients are asymptomatic at diagnosis, complicating early identification.12 Temporally, the onset of PBC may be first, concurrent, or follow SSc disease onset, with 7% to 17% of patients developing comorbidity.4 Diagnostically, PBC-SSc is more common in slightly older patients (seventh decade), women, and those with limited disease,4 and they exhibit a higher prevalence of calcinosis and telangiectasia than in SSc alone (Table 4).13 Hepatic disease progresses more slowly in SSc-PBC disease than in PBC only, although rates of mortality are similar due to extrahepatic morbidity of SSc-PBC.10 Data on AIH in SSc are scarce, although autoimmune disease is present in 14% to 44% of patients with AIH.14 An institutional retrospective review of 35 patients with biopsy-proved AIH identified only 2 patients with SSc, 1 of limited and 1 of diffuse cutaneous involvement, although subtypes are typically predominantly limited cutaneous systemic sclerosis (lcSSc) or overlap SSc syndrome, especially polymyositis (PM).15 Lastly, patients with SSc are at increased risk for malignancy, most commonly lung, liver, bladder, breast, and hematological. Although PBC is an independent risk factor for hepatocellular carcinoma, and patients with SSc have increased rates of PBC compared with the general population (2% versus 0.04%), there have been conflicting findings regarding actual rates of hepatic cancer observed in SSc in case-control16 and cohort studies.17 As a highly heterogenous disease, no single intervention has emerged as a grail of optimal management for SSc. Treatment regimens that address the full spectrum of disease consist of cytotoxic immunosuppressive therapies (e.g., methotrexate), and trials combine this with hematopoietic stem cell transplantation or total body radiation, with targeted therapies of interleukin-1, interleukin-6, and TGF-β, such as fresolimumab,18 under study. GI treatment is targeted to symptoms of dysmotility, and hepatic disease treatment does not differ from non-SSc-associated recommendations. Ideally, early recognition will allow for the most optimal medical care, interventions toward slowing the progression to permanent fibrotic organ damage. Perhaps counterintuitively, rapid progression is most common in early SSc disease, and spontaneous improvement in skin fibrosis can be seen in late stage, complicating surveillance of patient care and study outcomes. Algorithms such as DETECT have been developed for sensitive pulmonary arterial hypertension (PAH) screening, allowing early identification and mitigation of one of the key drivers of mortality in SSc.1 However, no similar detection schemes exist for GI pathologies, although serum markers of hepatic fibrosis are under study for correlation with SSc disease activity and severity.19 For the interim, screening for SSc in gastroenterology or hepatology patients may include routine inclusion of skin review of symptoms and CREST features (Sjögren sicca features, calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) because these occur more often in combined PBC-SSc, most especially calcinosis and telangiectasia.6, 13 Although no guidelines for hepatic disease screening are made by the ACR or the EULAR, attention should be paid to new elevated alkaline phosphatase or hypergammaglobulinemia, with low threshold to obtain an AMA or refer to gastroenterology.20 Improvement in the understanding of complex multiorgan diseases such as SSc requires multidisciplinary approaches. Liver disease is a rare complication of SSc and as such has not often been included in studies. This diagnostic and scientific role may fall to gastroenterologists. Concomitantly, it behooves hepatologists to consider concomitant autoimmune illness in patients with newly diagnosed PBC and AIH. With increased capture of SSc, more clear delineation of SSc subgroups and their diagnostic serology patterns may emerge and further our understanding of the pathophysiology, guiding new clinical queries and targeted therapies. In turn, SSc studies may further elucidate the elemental processes of hepatic fibrosis and regeneration. In conclusion, because the GI tract yields one of the highest symptom burdens in SSc disease, it may hold the key to unlocking some of the mysteries of SSc pathophysiology toward future understanding and treatments.