Acute severe presentations of autoimmune hepatitis (AIH) represent a challenge for the transplant community. As a disease, it is poorly characterized, and there is a weak evidence base to guide ...diagnosis and treatment. Early identification of acute severe AIH is key because it determines the initiation of corticosteroids, which can be lifesaving. However, their use in this setting remains controversial. The Model for End‐Stage Liver Disease score, severity of coagulopathy, and grade of encephalopathy may be predictors of outcome with corticosteroid therapy. The optimal timing of liver transplantation (LT) can be difficult to determine and, as such, the decision to proceed to transplantation should not be delayed by protracted courses of corticosteroids. The aim of this review is to better characterize this subset of patients; to differentiate them clinically, serologically, and histologically from chronic AIH and other causes of acute liver failure; and to present the role, predictors, and optimal timings of corticosteroid therapy and LT. Although this review is specific to adults, many principles hold true for the pediatric population.
Abstract This review concentrates on autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, characterized by inflammatory liver histology, elevated transaminase levels, ...circulating non-organ-specific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known aetiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1, while antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. There is a female predominance in both types. AIH is particularly aggressive in children/adolescents, progressing rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission and long-term survival. In childhood/adolescence, sclerosing cholangitis with strong autoimmune features, including interface hepatitis and serological features identical to AIH type 1, is as prevalent as AIH, but it affects boys and girls equally. The differential diagnosis relies on cholangiographic studies. In autoimmune sclerosing cholangitis, liver parenchymal damage responds satisfactorily to immunosuppressive treatment, whereas bile duct disease progresses in 50% of cases, leading to a worse prognosis and higher transplantation requirement; it has a higher recurrence rate after transplant than AIH. AIH can arise de novo in patients transplanted for non-autoimmune liver disease. Post transplant de novo AIH affects children and adults and responds well to the same treatment schedule used for classical AIH, but not to that used for acute rejection.
Wilson disease is an autosomal recessive disease of liver copper metabolism with predominant hepatic and neurological manifestations. Long-term data on the clinical follow-up and treatment efficacy ...are limited due to the low frequency of the disease. We evaluated a large cohort of Wilson disease patients from Northern Portugal during a 20-year follow-up period.
Twenty-four patients, diagnosed from 1975 to 2020 in a tertiary care center in Portugal, were retrospectively evaluated according to their clinical presentation, therapies and outcomes.
Most of the patients were males (54%), with a median age at diagnosis of 19 years old (interquartile range 15-25). The main manifestations of Wilson disease were hepatic (71%) and neurological (25%). Family history was positive in 5 (21%) patients. Four patients (17%) presented with acute liver failure and fifteen (63%) individuals had cirrhosis at diagnosis. Penicillamine therapy was used by 11 (46%) patients, while trientine and zinc were given to 8 (33%) and 1 (4%) patient, respectively. Ten (42%) individuals underwent liver transplantation. The majority of patients (83%) had stable disease or improved outcomes during follow-up.
This is the largest cohort of adult patients with Wilson disease reported in Northern Portugal. We show that Wilson disease has favorable outcomes with long overall survival, assuming adherence to therapy and lack of other insults to their liver.
Hepatocellular carcinoma (HCC), the dominant primary malignancy of the liver, has almost invariably a fatal outcome that can be averted only by early diagnosis and treatment. While the close ...association of HCC with chronic viral hepatitis and alcohol abuse has impacted favourably on screening and treatment of this deadly tumour, at the same time it has long obscured the etiologic role of autoimmune liver diseases. Recently, a systematic analysis of 25 published cohorts disclosed a 3.1 × 1000 patients/year incidence of HCC in autoimmune hepatitis patients that tripled in those with cirrhosis. HCC is also a sequela of primary biliary cholangitis, where the incidence is more relevant in males, those with advanced liver disease and nonresponders to ursodeoxycholic acid therapy. Cholangiocarcinoma (CCA), the second ranking primary cancer of the liver, is also on the rise with its intrahepatic pattern, in part reflecting an association with chronic liver diseases of diverse aetiology. In the USA and northern Europe, perihilar CCA is a frequent complication of primary sclerosing cholangitis, a cholestatic disorder thought to be immune mediated. International Guidelines clearly recommend HCC screening with abdominal ultrasonography every 6 months in autoimmune cirrhotic patients. While surveillance of patients with autoimmune liver disorders who are at risk of HCC affects both early diagnosis and radical therapy of this tumour, this is not the case for CCA, where early diagnosis is challenged by the lack of sensitive and accurate tests for screening.
Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and ...PSC the targets of the autoimmune attack are the biliary epithelial cells.Persistent liver injury,associated with chronic AILD,leads to un-resolving inflammation,cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts.Liver cirrhosis,and the resultant loss of normal liver function,inevitably ensues.Patients with cirrhosis have higher risks or morbidity and mortality,and that in the decompensated phase,complications of portal hypertension and/or liver dysfunction lead to rapid deterioration.Accurate diagnosis and monitoring of cirrhosis is,therefore of upmost importance.Liver biopsy is currently the gold standard technique,but highly promising non-invasive methodology is under development.Liver transplantation(LT) is an effective therapeutic option for the management of endstage liver disease secondary to AIH,PBC and PSC.LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy;in addition,LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.
Background & Aims IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis (IgG4-SC/AIP) are characterized by massive lymphoplasmacytic infiltration including Th2 and regulatory T cells ...(Tregs). This study was conducted to address which chemotactic factors are involved in this condition. Methods Chemokine expression profiles in tissue were examined in IgG4-SC/AIP (n = 17), classical primary sclerosing cholangitis (IgG4low PSC, n = 17), PSC with elevated serum/tissue IgG4 levels (IgG4high PSC, n = 5), and primary biliary cirrhosis (n = 7). We focused on five chemotactic factors/receptors (CCL1-CCR8, CCL17/CCL22-CCR4), given that CCR4 and CCR8 are predominantly expressed in both Th2 and Tregs. Results In conjunction with higher expression levels of IL-4 and IL-10, expression values of CCL1 and CCR8 transcripts were significantly higher in IgG4-SC/AIP than in IgG4low PSC ( p = 0.002) and IgG4high PSC ( p = 0.023). CCL1 and CCR8 were also overexpressed in IgG4high PSC than in IgG4low PSC ( p = 0.023). No difference was seen for CCL17, CCL22, and CCR4. In situ hybridization revealed CCL1 to be predominantly expressed in the pancreatic duct epithelium, peribiliary glands, and vascular endothelial cells including the ones involved in obliterative phlebitis in IgG4-SC/AIP, in contrast to IgG4high PSC where this chemotactic factor was positive in several infiltrating lymphocytes. These CCL1-expressing sites were infiltrated by CCR8+ lymphocytes. On immunohistochemistry, GATA3+ Th2 lymphocytes and FOXP3+ Tregs were significantly larger in number in IgG4-SC/AIP, with the GATA3+ /T-bet+ cell ratio to be shifted in favour of Th2 in periductal and perivascular areas. Conclusions CCL1-CCR8 interaction may play a critical role in lymphocytic recruitment in IgG4-SC/AIP, leading to duct-centred inflammation and obliterative phlebitis.
Update on Autoimmune Hepatitis Liberal, Rodrigo; Vergani, Diego; Mieli-Vergani, Giorgina
Journal of clinical and translational hepatology,
03/2015, Volume:
3, Issue:
1
Journal Article
Open access
Autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, is characterized by inflammatory liver histology, elevated transaminase levels, circulating nonorganspecific ...autoantibodies, and increased levels of immunoglobulin G, in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels. AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine, with symptom free long-term survival for the majority of patients. For those who do not respond to standard treatment, or who are difficult-to-treat, mycophenolate mofetil and, in the absence of a response, calcineurin inhibitors should be tried in addition to steroids. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.
Pathogenesis of autoimmune hepatitis Liberal, Rodrigo, MD; Longhi, Maria Serena, MD, PhD; Mieli-Vergani, Giorgina, MD, PhD, FRCP ...
Baillière's best practice & research. Clinical gastroenterology,
12/2011, Volume:
25, Issue:
6
Journal Article
Peer reviewed
The mechanisms underlying the pathogenesis of autoimmune hepatitis are not fully understood, though there is growing evidence that genetic predisposition, molecular mimicry and/or impairment of ...regulatory T-cells are involved in the initiation and perpetuation of the autoimmune liver attack. The histological picture of interface hepatitis, characterized by a dense portal mononuclear cell infiltrate, was the first to suggest an autoaggressive cellular immune attack in the pathogenesis of this condition. Liver damage is likely to be orchestrated by CD4pos T-cells recognizing an autoantigenic liver peptide. For autoimmunity to arise, the peptide must be presented by antigen-presenting cells to naïve CD4pos T-helper (Th0) cells. Once activated, Th0-cells can differentiate into Th1-, Th2-, or Th17-cells, initiating a cascade of immune reactions that are determined by the cytokines they produce. Autoantigen recognition and the above effector mechanisms are opposed by regulatory T-cells, a cell subset numerically and functionally impaired in autoimmune hepatitis.
Summary
Background
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative pathogen of coronavirus disease 2019 (COVID‐19), became a global threat to human health. Liver ...impairment has been frequently reported as a common manifestation, although its clinical significance is still unclear, particularly in patients with underlying chronic liver disease (CLD).
Aims
To summarise the changes in liver function tests during SARS‐CoV‐2 infection and the impact of COVID‐19 in patients with underlying CLD.
Methods
A literature review using online database PubMed was done using the search terms “SARS‐CoV‐2”, “COVID‐19”, “liver”, “cirrhosis” and “liver transplantation”.
Results
COVID‐19 is frequently associated with different degrees of abnormal liver function tests, most notably transaminases, which are usually transitory and of mild degree. Available evidence suggests that liver injury may result from direct pathogenic effect by the virus, systemic inflammation or toxicity from commonly used drugs in this subset of patients. SARS‐CoV‐2 infection in children is associated with minimal or no increase in liver enzymes, thus the presence of abnormal liver function tests should trigger evaluation for underlying liver diseases. Although it seems that patients with CLD are not at greater risk for acquiring the infection, those with cirrhosis, hepatocellular carcinoma, non‐alcoholic fatty liver disease, autoimmune liver diseases or liver transplant may have a greater risk for severe COVID‐19.
Conclusions
Abnormal liver function tests during the course of COVID‐19 are common, though clinically significant liver injury is rare. Further research is needed focusing on the effect of existing liver‐related comorbidities on treatment and outcome of COVID‐19.
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