Prevalence of Acute on Chronic Liver Failure in Autoimmune Hepatitis, Treatment Response and Mortality Burden Assessment: A Region-Predominant Systematic Review and Meta-Analysis.

Acute-on-chronic liver failure (ACLF) is a global health problem. Little scientific evidence exists on its prevalence in autoimmune hepatitis. Treatment response and mortality outcomes have also been reported differently. The study was conducted to estimate the overall prevalence of ACLF among patients with autoimmune hepatitis (AIH) and determine the associated treatment response and mortality. We scrutinized wide literature in Scopus, PubMed, Embase, Web of Science, and Cochrane, and assessed published articles completely, studies performed and reported from around the globe, until December 07, 2023, according to the PROSPERO registered protocol (CRD42023412176). Studies (retrospective and prospective cohort study type) that stated the ACLF development among established AIH cases were considered. Features of the study, duration of follow-up, and numeric patient information were retrieved from the studies included. The research paper quality was checked for risk of bias. Random effect meta-analysis with metaregression and subsection scrutinies were performed with R. The main outcome was the collective prevalence of ACLF in the AIH patients, whereas treatment response and mortality in AIH-associated ACLF were secondary outcomes. Six studies were involved with confirmed diagnoses in 985 AIH patients for the data synthesis. The pooled prevalence of ACLF in the explored patients was 12% (95% CI: 8-17) ( P =0.01). Heterogeneity was found to be high in the present meta-analysis ( I2 =72%; P < 0.01). For the secondary endpoint analysis, the pooled prevalence of complete remission at 1-year follow-up was 71% (0.52; 0.85), and mortality from the ACLF-AIH patient population was 32% (95% CI: 18-50). Sensitivity analysis showed no influence on the overall estimations of the pooled prevalence of ACLF by omitting studies one by one. One in 10 AIH patients likely present with ACLF. The response to treatment is seen in two-thirds of patients, and mortality is high.

Autoimmune hepatitis in teenage pregnancy with good obstetric outcome.

Autoimmune hepatitis (AIH) is a rare liver disorder having long-standing inflammatory features. It classically affects women of reproductive age and can have adverse maternal and fetal outcomes during the pregnancy. The course of the disease is unpredictable and there have been flares even in stable patients. There are limited reports of its management in pregnancy. Furthermore, clinicians may encounter more pregnancies complicated by AIH due to advances in the treatment of AIH. We report a case of unplanned pregnancy in a young teenager who had been diagnosed with AIH. This case report summarises the risks, investigations, treatment and prevention of complications to achieve a favourable outcome in pregnancy. We highlight the importance of tight surveillance by a multidisciplinary team involving maternal medicine specialists and hepatology teams to achieve a good obstetric outcome in a district hospital like ours.

Coexistence of metabolic-associated fatty liver disease and autoimmune or toxic liver disease.

Fatty liver disease (FLD) affects approximately 25% of global adult population. Metabolic-associated fatty liver disease (MAFLD) is a term used to emphasize components of metabolic syndrome in FLD. MAFLD does not exclude coexistence of other liver disease, but impact of coexisting MAFLD is unclear. We investigated prevalence and characteristics of MAFLD in patients with biopsy-proven autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), or toxic liver disease. Liver histopathology and clinical data from Helsinki University Hospital district (1.7 million inhabitants) between 2009 and 2019 were collected from patients with AIH, PBC, PSC, or toxic liver disease at the time of diagnosis. MAFLD was diagnosed as macrovesicular steatosis ≥5% together with obesity, type-2 diabetes, or signs of metabolic dysregulation. Of 648 patients included, steatosis was observed in 15.6% (n = 101), of which 94.1% (n = 95) was due to MAFLD. Prevalence of coexisting MAFLD in the four liver diseases varied between 12.4 and 18.2% (P = 0.483). Fibrosis was more severe in MAFLD among patients with toxic liver disease (P = 0.01). Histopathological characteristics otherwise showed similar distribution among MAFLD and non-FLD controls. Alcohol consumption was higher in MAFLD group among patients with AIH or PBC (P < 0.05 for both). In AIH, smoking was more common in patients with coexisting MAFLD (P = 0.034). Prevalence of coexisting MAFLD in other primary liver diseases is lower than reported in general population. Histopathology of MAFLD patients did not clearly differ from non-FLD ones. Alcohol and smoking were associated with MAFLD in AIH.

Acute liver failure histopathology: A 5-year retrospective study.

BACKGROUND: Acute liver failure (ALF) is a rare, life-threatening disease of diverse etiology. It is defined as severe acute liver injury for fewer than 26 weeks' duration with encephalopathy and impaired synthetic function (international normalized ratio [INR] of 1.5 or higher) in a patient without cirrhosis or pre-existing liver disease. The diagnosis rests mainly on the clinical ground with wide range of pathological features. The present study seeks to explore the diverse histological patterns observed in cases for ALF and assess their usefulness in determining the underlying causes for the condition. METHODOLOGY: A retrospective cross-sectional study was conducted among patients of ALF who underwent liver transplant and transjugular liver biopsy over a five-year period. From 1082 explant liver and 2446 liver biopsies, 22 cases of ALF (10 explants and 12 liver biopsies) were included in the study. Clinical and laboratory details were retrieved and histological findings were reviewed. RESULT: Age ranged from 10 to 72 years (mean age, 40 years). There was a female predominance with a male:female ratio of 1:1.7. The commonest cause for ALF was virus-induced hepatocellular damage in 36.3% (eight patients), followed by autoimmune hepatitis in 22.7% (five patients), drug-induced liver injury (DILI) in 18.1% (four patients), cryptogenic in 13.6% (three patients) and ischemic injury secondary to large vein thrombosis in 9.0% (two) patients. The histological patterns identified were categorized into six categories. A more comprehensive morphological evaluation was conducted specifically for cases of ALF associated with autoimmune hepatitis (AIH) and compared with other cases of ALF. CONCLUSION: In summary, our present study illustrates a morphological overlap in various patterns for the purpose of etiological assessment. In cases of AIH ALF, the presence of portal plasma cell infiltrate and central perivenulitis were identified as significant histological features to guide diagnosis.

Liver manifestation of patients with celiac disease: A single center experience.

OBJECTIVES: Characterize the clinicopathologic features of liver biopsies from patients with celiac disease (CD). METHODS: Single center, retrospective search for liver biopsies from patients with CD. RESULTS: 36 unique patients were included, median age of 46 years (range: 2-75), including 5 pediatric patients, with an overall female predominance (25, 69 %) but in in children a male predominance was seen (p = 0.023). Most cases (75 %) had an underlying condition including autoimmune hepatitis (AIH) (11 %), AIH/primary biliary cholangitis (PBC) overlap (3 %) and PBC (3 %). The median body mass index was 28, with 4 (11 %) underweight and 22 (61 %) overweight/obese patients. The most common histologic pattern was steatosis (18, 50 %), considered severe in 5 (14 %) and in 7 (19 %) regarded as steatohepatitis. The other histologic patterns included a nonspecific portal and/or lobular inflammation ("celiac hepatitis") in 9 cases (25 %), autoimmune hepatitis (3, 8 %), chronic cholestatic pattern (3, 8 %), chronic hepatitis (1, 3 %), acute lobular hepatitis (1, 3 %) and stablished cirrhosis (1, 3 %). Additionally, 2 of the cases with steatosis show cirrhosis. CONCLUSIONS: The biopsy findings from patients with CD are heterogenous and in most represent a concomitant underlying disease, particularly metabolic dysfunction-associated steatotic liver disease. Additionally, CD injury should remain in the differential diagnosis in liver biopsies with a nonspecific portal and/or lobular inflammation.

Dominant stricture in paediatric-onset primary sclerosing cholangitis is associated with impaired prognosis in a long-term follow-up.

BACKGROUND AND OBJECTIVES: The impact of dominant stricture (DS) on the outcomes of paediatric-onset primary sclerosing cholangitis (PSC) is unknown. This study was aimed at investigating the impact of DS on the clinical course and prognosis of patients with paediatric-onset PSC. METHODS: Patients with paediatric-onset PSC diagnosed between January 1993 and May 2017 were identified from hospital records or our PSC registry. Data including clinical, laboratory, cholangiography, and cytology at diagnosis and during follow-up (until July 2023) were reviewed. We graphed the Kaplan-Meier failure function and fitted crude and multivariable Cox model to calculate hazard ratios (HR) and 95% confidence intervals (CI) for selected variables. In these analyses, DS was treated as a time-varying variable. RESULTS: We identified 68 patients (42 males) with paediatric-onset PSC (median age at diagnosis 15 years). The median follow-up was 13 years and the median age at the last follow-up was 27 years. In total, 35 (51%) had concomitant autoimmune hepatitis. DS was diagnosed in 33 patients (48%): in eight at the time of PSC diagnosis (12%) and in 25 (37%) by the end of follow-up. In patients with DS, two developed cirrhosis, seven were transplanted and one patient was operated for a biliary mass with low-grade dysplasia. In patients without a DS, two developed cirrhosis, and four were transplanted; one female was excluded from survival analysis because she already had cirrhosis at the time of PSC diagnosis. Cirrhosis or biliary dysplasia or needing liver transplantation for these indications were more frequent after the development of DS (10/33, adjusted HR 4.26, 95%CI: 1.26-14.4). No cholangiocarcinomas or deaths occurred during the follow-up. CONCLUSIONS: DS was present at diagnosis or developed during follow-up in about half of the patients with paediatric-onset PSC and was associated with impaired outcome.

Liver cirrhosis in a patient with alcohol dependence and autoimmune hepatitis.

BACKGROUND: Liver cirrhosis is the end-stage entity for a wide variety of chronic liver pathologies. These include viral hepatitis B and C, alcoholic liver disease, non-alcoholic fatty liver disease, hemochromatosis, Wilson disease, autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis. In the majority of cases, liver cirrhosis remains completely asymptomatic until acute decompensation occurs. Patients may present complications of portal hypertension such as gastro-esophageal varices and upper digestive hemorrhage, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, or hepato-renal syndrome. Establishing the right etiology of cirrhosis is of paramount importance as it helps the treating physician plan the best suitable treatment options and also improves overall outcome. CASE REPORT: We present a case of a chronic alcohol consumer, which, over time, resulted in alcoholic cirrhosis. Initial diagnosis comprised of alcoholic liver disease. However, a further look into the medical history of the patients indicated the presence of underlying autoimmune liver disease, such as autoimmune hepatitis, which might have also contributed to the chronic liver injury. CONCLUSIONS: Multiple factors can lead to liver cirrhosis. Although the most commonly found entity is alcoholism, it cannot be taken as a thumb rule for the only possible etiology. In-depth analysis and proper differential diagnosis should be carefully conducted in order not to miss out on other possible causes. As seen in our case, where an underlying autoimmune hepatitis was found to be the culprit, but due to a long history of alcohol consumption, it was masked at first instance.

Outcomes and management in paediatric autoimmune hepatitis presenting as acute liver failure: Individual patient data meta-analysis.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) in children presenting in acute liver failure (ALF) can be fatal and often requires liver transplantation (LTx). This individual patient data meta-analysis (IPD) aims to examine management and outcomes of this population, given the lack of large cohort studies on paediatric AIH first presenting as ALF (AIH-ALF). METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement using PubMed and Excerpta Medica dataBASE, and included English studies published between 2000 and 2020. The study included patients under 21 years of age, diagnosed with type 1 or 2 AIH and presenting with ALF. Data extracted included clinical and biochemical characteristics, interventions, and outcomes. RESULTS: Three hundred and thirty eligible patients from 61 studies were identified, with an additional five patients from our institution. The majority were female (66.8%), with a median age of 10. Overall, 59.7% achieved native liver survival (NLS), 35% underwent LTx, and 5% died before LTx. The use of corticosteroids with non-steroid immunomodulators increased the likelihood of NLS by 2.5-fold compared to corticosteroids alone. AIH-1 was associated with 3.3-fold odds for NLS, compared to AIH-2. However, on multivariate analysis, only AIH-1 was identified as an independent predictor for NLS (OR 3.8 [95% CI 1.03-14.2], p = .04). CONCLUSION: While corticosteroids and non-steroid immunomodulators treatment may offer enhanced probability of achieving NLS, treatment regimens for AIH-ALF may need to consider patient-specific factors, especially AIH type. This highlights the potential for NLS in AIH-ALF and suggest a need to identify biomarkers which predict the need for combination immunosuppression to avoid LTx.

Quantitative measurements of M2BPGi depend on liver fibrosis and inflammation.

BACKGROUND: The relationship between liver fibrosis and inflammation and Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with chronic liver disease (CLD) other than hepatitis C remains uncertain, owing to the limitations of qualitative methods. Here, we evaluated the influence of liver fibrosis and inflammation on quantitative M2BPGi (M2BPGi-Qt) in CLD, considering each etiology. METHODS: We recruited 1373 patients with CLD. To evaluate the influence of liver fibrosis and inflammation on M2BPGi-Qt levels, we assessed M2BPGi-Qt levels at each fibrosis and activity stage within different etiologies of CLD based on pathological findings. Subsequently, we evaluated if the accuracy of fibrosis staging based on M2BPGi-Qt could be improved by considering the influence of liver inflammation. RESULTS: In patients with viral hepatitis, non-alcoholic fatty liver disease, and primary biliary cholangitis, the median M2BPGi-Qt levels increased liver fibrosis progression. Median M2BPGi-Qt levels were not associated with the degree of fibrosis in patients with autoimmune hepatitis (AIH). Median M2BPGi-Qt levels increased with the progression of liver activity in all etiologies. A significant difference was found at each stage in AIH. Considering the liver inflammation, we established an algorithm, M2BPGi-Qt, to determine the alanine aminotransferase-to-platelet ratio (MAP-R) in liver cirrhosis (LC). The area under the receiver operating characteristic curve (AUC) of MAP-R was higher than that of the M2BPGi-Qt for detecting LC (AUC MAP-R = 0.759 and M2BPGi-Qt = 0.700, p < 0.001). CONCLUSIONS: The quantitative measurement system for M2BPGi depends on liver fibrosis and inflammation, regardless of etiology. Liver inflammation complicates the interpretation of M2BPGi-Qt results when assessing the fibrosis stage.

Previous hepatitis E virus infection is associated with increased liver stiffness in patients with autoimmune hepatitis.

INTRODUCTION: Autoimmune hepatitis (AIH) is a chronic, progressive liver disease that, in most cases, may require lifelong immunosuppression. Hepatitis E virus (HEV) is a leading cause of acute, typically self­limited hepatitis worldwide, although immunocompromised patients may develop chronic hepatitis. OBJECTIVES: We aimed to evaluate the impact of HEV seropositivity on the clinical course of AIH. PATIENTS AND METHODS: The study involved a group of 374 adult patients with AIH (68% women; median [interquartile range] age, 34 [18-83] years; 38% with liver cirrhosis). Serum HEV immunoglobulin (Ig) G and IgM antibodies were measured by enzyme­linked immunosorbent assay, liver fibrosis was assessed by liver stiffness measurement (LSM), and liver cirrhosis was confirmed with liver histology or LSM. RESULTS: Fifty­five patients (15%) with AIH were HEV IgG­positive. These patients were older (P <0.001), had higher body mass index, and higher value of LSM (both P <0.05). In a multivariable model including the levels of alanine aminotransferase and IgG, the HEV seropositive status was associated with an increased risk of advanced liver fibrosis with odds ratio of 3.69 (95% CI, 1.26-10.77; P = 0.02), as reflected by liver stiffness equal to or above 10.5 kPa. HEV IgG seropositivity was, however, not linked with the type of treatment or worse AIH outcome. Seroprevalence of HEV in the patients with AIH was lower than in the general population of Polish blood donors (43%). CONCLUSIONS: Patients with AIH and HEV IgG­positive status seem to be at risk of more advanced liver fibrosis. However, the overall seroprevalence of HEV IgG is lower in patients with AIH than in blood donors in Poland.

Simultaneous occurrence of autoimmune hepatitis and autoimmune hemolytic anemia after COVID-19 infection: case report and literature review.

Various autoimmune diseases have been reported to develop as a result of a coronavirus disease 19 (COVID-19) infection. There have been some reports of COVID-19-triggered autoimmune hepatitis and autoimmune hemolytic anemia infection, but none have reported simultaneous onset of these diseases. A 15-year-old girl was admitted to our hospital with severe liver injury and anemia. Three weeks before admission, her father was diagnosed with COVID-19, after which she became aware of a sore throat. Two weeks later, she visited her doctor for malaise. She was referred to our hospital due to severe anemia, elevated hepatobiliary enzymes, and jaundice. A COVID-19 polymerase chain reaction test was positive at the time of referral. She was diagnosed with autoimmune hemolytic anemia based on decreased hemoglobin and haptoglobin, positive direct Coombs test, and increased urinary urobilinogen. Blood tests were positive for antinuclear antibodies, and a liver biopsy revealed interface hepatitis and plasma cell infiltration, consistent with autoimmune hepatitis. Based on these findings, a diagnosis of autoimmune hepatitis and autoimmune hemolytic anemia triggered by COVID-19 infection was made. Steroid therapy was initiated, which resulted in rapid improvement of blood markers and symptoms.

Management of hepatocellular carcinoma, an important cause of death in Japanese autoimmune hepatitis patients.

BACKGROUND: Hepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH) was considered rare but is increasing with prolonged prognosis. Its impact on the overall prognosis of AIH is unknown, and treatment has not been established. AIM: To investigate the risk factors and prognosis of HCC in patients with AIH and identify appropriate management strategies. METHODS: We studied patients with AIH including background liver disease, sex, age, complications, treatment, response to treatment, liver fibrosis, prognosis, and treatment. RESULTS: In 131 patients, deaths due to liver failure were more common early after the onset of AIH; however, deaths due to HCC increased gradually. HCC was observed in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis at onset, 11; median time to carcinogenesis, 7 years). Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate analysis (odds ratio, 41.36; p < 0.0001) and cumulative cancer rates were high. Multidisciplinary therapy other than immune checkpoint inhibitors was administered as treatment for HCC. Two of the three patients who used molecular-targeted drugs discontinued the treatment because of adverse events. CONCLUSION: HCC is an important cause of death in patients with AIH. Currently available drug therapies are limited and early detection is desirable. TRIAL REGISTRATION: This trial was retrospectively registered in the Ethics Committee of Kagawa University School of Medicine under the identifier 2019 - 238, registered on 4 Feb 2020.

Unprecedented complexity of six coexisting autoimmune diseases: A case report.

INTRODUCTION: Autoimmune disorders often exhibit interconnectedness, although encountering multiple autoimmune conditions in a single patient is uncommon. Multiple autoimmune syndrome is characterized by the presence of at least three distinct autoimmune diseases in an individual. This report outlines the case of a middle-aged woman diagnosed with autoimmune thyroiditis, Sjögren's syndrome, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, and antisynthetase syndrome. Additionally, it includes a literature review encompassing multiple autoimmune syndromes involving five or more autoimmune diseases. OBSERVATION: A 57-year-old woman, with no previous medical history, presented with fever, extensive muscle weakness, progressive exertional dyspnea, inflammatory polyarthralgia, dysphagia, and dry mouth. Clinical examination revealed muscular deficit in the scapular and pelvic girdles, distal muscular deficit, synovitis in the wrists, and features indicative of "mechanic's hand". Laboratory examinations showed cytolysis, cholestasis, elevated muscle enzymes, hypergammaglobulinemia and elevated thyroid stimulating hormone. Immunoassays showed positive results for antinuclear antibodies, anti-histidyl-t-RNA synthetase, anti-Sjögren's-syndrome-related antigen A, anti-ribonucleic-acid-polymerase-III-RP155, anti-fibrillarin, anti-mitochondrial, anti-liver/kidney microsomal type 1, anti-glycoprotein 210, and anti-thyroid peroxidase antibodies. Further investigations led to the diagnosis of a multiple autoimmune syndrome involving autoimmune thyroiditis, Sjögren's syndrome, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, and antisynthetase syndrome. The patient received treatment with intravenous immunoglobulins, corticosteroids, azathioprine, and ursodeoxycholic acid, which resulted in favorable clinical and biological outcomes. CONCLUSION: This patient presented with six concurrent distinct autoimmune disorders, categorizing this case as a type two multiple autoimmune syndrome. The identification of antisynthetase syndrome notably distinguishes this case.

[Clinicopathological features of Sjogren's syndrome complicated with liver injury].

Objective: To study the clinicopathological features of Sjogren's syndrome (SS) with liver injury and to improve the understanding of this disease. Methods: Forty-nine patients with SS complicated with liver injury were collected from Beijing Ditan Hospital, Capital Medical University from October 2008 to January 2022. All patients underwent ultrasound-guided liver biopsy, and all specimens were stained with HE. The histopathologic characteristics were observed and the pathologic indexes were graded. Immunohistochemical stains for CK7, CK19, CD38, MUM1 and CD10 were performed by EnVision method; and special histochemical stains for reticulin, Masson's trichrome, Rhodanine, Prussian blue, periodic acid Schiff (PAS) and D-PAS stains were conducted. Results: The age of patients ranged from 31 to 66 years, including 3 males and 46 females. SS combined with drug-induced liver injury was the most common (22 cases, 44.9%), followed by autoimmune liver disease (13 cases, 26.5%, including primary biliary cholangitis in eight cases, autoimmune hepatitis in 3 cases, and PBC-AIH overlap syndrome in 2 cases), non-alcoholic fatty liver disease (NAFLD, 9 cases, 18.4%) and other lesions (5 cases, 10.2%; including 3 cases of nonspecific liver inflammation, 1 case of liver amyloidosis, and 1 case of porto-sinusoidal vascular disease). Among them, 28 cases (57.1%) were associated with obvious interlobular bile duct injury, mainly in SS combined with PBC group and drug-induced liver injury group. Twenty-three cases (46.9%) were associated with hepatocyte steatosis of varying degrees. In SS with autoimmune liver disease group, ISHAK score, degree of fibrosis bile duct injury, bile duct remodeling, lymphocyte infiltration of portal area, and plasma cell infiltration, MUM1 and CD38 expression; serum ALP and GGT, IgM; elevated globulin; positive AMA, proportion of AMA-M2 positive and IgM positive were all significantly higher than those in other groups(all P<0.05). Serum ALT, direct bilirubin and SSA positive ratio in SS combined with drug liver group were significantly higher than those in other groups(all P<0.05). The serum total cholesterol level in SS combined with PBC group (P=0.006) and NALFD group (P=0.011) were significantly higher than those in other groups (P<0.05). Conclusions: The pathologic manifestations of SS patients with liver injury are varied. The inflammatory lesions of SS patients with autoimmune liver disease are the most serious, and the inflammatory lesions of SS patients with non-alcoholic fatty liver disease and non-specific inflammation are mild. Comprehensive analysis of liver histopathologic changes and laboratory findings is helpful for the diagnosis of SS complicated with different types of liver injury.

Autoimmune Liver Diseases and Rheumatoid Arthritis-Is There an Etiopathogenic Link?

Rheumatoid arthritis (RA) is a systemic immune-mediated disease that, in addition to the articular involvement, can have extra-articular manifestations. Even though liver damage in RA is not very common, associated autoimmune liver diseases (AILDs) may occur. The most common AILD associated with RA is primary biliary cirrhosis (PBC), followed by autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). There are common underlying mechanisms that play a role in the emergence of autoimmunity and inflammation in both rheumatic and autoimmune liver diseases. Genetic studies have revealed the existence of several common disease-associated genes shared between RA and AILDs, and infectious triggers, particularly those associated with recurrent or complicated urinary tract infections, are also speculated to be potential triggers for these conditions. Moreover, these diseases share common serologic patterns characterized by the presence of specific autoantibodies and hyper-gammaglobulinemia. In this study, we focus on reviewing the association between RA and AILDs regarding the prevalence and possible etiopathogenic link.

Prevalence of autoimmune thyroiditis among children with autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is an organ specific autoimmune disease, which can manifest at any age of life. there is a high prevalence of extrahepatic autoimmune diseases in patients with AIH. Autoimmune thyroid diseases (ATDs) are the most frequent extrahepatic autoimmune disorders among patients with AIH. Aim of work is to detect the frequency of ATDs among Egyptian children with AIH. METHODS: This research is a cross-sectional study conducted on 58 children with AIH aged ≤ 18 years. All patients were tested for free triiodothyronine (FT3), free tetraiodothyronine (FT4), thyroid stimulating hormone (TSH), anti-thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG). Thyroid ultrasound (US) and thyroid scan were performed for patients with abnormal thyroid profile, borderline values, positive anti-TPO or anti-TG. RESULTS: The mean ± standard deviation (SD) for the age of the patients was 11.3 ± 4.5 years. Out of 58 patients of AIH, 28 patients (48.3%) had associated other autoimmune diseases. Autoimmune thyroiditis was the most common associated autoimmune disease being present in 10 patients (17.2%). The thyroid status of AIT patients showed that 6 patients (60%) were euthyroid, 3 patients (30%) had subclinical hypothyroidism and only one patient (10%) was hyperthyroid. CONCLUSION: Autoimmune hepatitis in Egyptian children is commonly associated with other autoimmune diseases. Autoimmune thyroiditis is the most common to be associated with AIH in pediatric patients. As it is not usually clinically manifesting, regular screening for AIT in children with AIH is mandatory.

Elevated serum HE4 levels as a novel biomarker of disease severity and hepatic fibrosis in autoimmune hepatitis.

BACKGROUND: Human epididymis protein 4 (HE4) has been identified as a biomarker for renal fibrosis. This study aimed to evaluate the role of HE4 in the diagnosis and determination of disease severity and hepatic fibrosis in autoimmune hepatitis (AIH). METHODS: Serum HE4 levels were determined via electrochemiluminescence immunoassays in 60 healthy controls and 109 AIH patients (43 without liver cirrhosis and 66 with liver cirrhosis). Liver biopsy was performed on 56 of 109 enrolled patients. We conducted a 5-year follow-up survey of 53 enrolled patients. All continuous variables were reported as median (25th-75th percentile). RESULTS: Serum HE4 levels were significantly elevated in autoimmune hepatitis with liver cirrhosis (AIH-LC) patients compared with AIH patients and healthy controls [98.60 (74.15-139.08) vs 73.50 (59.88-82.00) vs 48.75 (43.38-52.93) pmol/L, p = 0.004]. The serum HE4 levels showed a positive correlation with the METAVIR scoring system in patients with liver biopsy (r = 0.711, p < 0.001). Serum HE4 levels were significantly elevated in Child-Pugh class C patients compared with Child-Pugh class B patients and Child-Pugh class A patients [106.50 (83.46-151.25) vs 110.00 (73.83-166.75) vs 77.03 (72.35-83.33) pmol/L, p = 0.006]. The diagnostic sensitivity and specificity of serum HE4 for evaluating liver cirrhosis were 69.7 % and 79.07 %, respectively, with a cutoff value of 82.34 pmol/L in enrolled patients. The logistic regression analysis showed that high levels of HE4 (≥82.34 pmol/L) were associated with AIH-LC (OR = 8.751, 95 % CI = 1.412-54.225, p = 0.020). The Kaplan-Meier curves demonstrated that high levels of serum HE4 (≥82.34 pmol/L) were associated with poor outcome (log-rank p = 0.037, HR = 0.372, 95 % CI = 0.146-0.946). CONCLUSIONS: Serum HE4 levels were found to be elevated in AIH-LC patients and exhibited a strong correlation with the severity of hepatic fibrosis, thus supporting their potential clinical value as a novel biomarker of disease severity and hepatic fibrosis in AIH.

Changing etiological spectrum of acute liver failure.

BACKGROUND AND OBJECTIVES: Acute liver failure (ALF) is an uncommon but potentially dramatic syndrome characterized by massive hepatic necrosis and has a very high mortality rate of 50% to 75% without liver transplantation. This study is aimed at analyzing the etiological spectrum of ALF patients and compare these with ALF mimics such as malaria, dengue fever and other tropical infectious diseases. METHODS: The study population included patients who presented with ALF and ALF mimics in a tertiary care center over two years. We retrospectively analyzed the patient case files and a comparison was made concerning the baseline demographic details, clinical profile, laboratory values and outcomes. RESULTS: Sixty-three patients were assessed, with 32 in ALF and 31 in ALF mimics group. The most common cause for ALF was hepatitis A virus (25%), followed by hepatitis B virus (18.7%), drug-induced liver injury (12.7%), autoimmune hepatitis (12.5%), hepatitis E virus (9.3%) and Wilson's disease (6.25%). In the ALF mimics group, malaria (58.06%) was the most common cause, followed by dengue fever (16.1%), leptospirosis (12.9%) and scrub typhus (12.9%). Patients in the ALF mimics group had significantly higher incidence of fever (p = 0.001), hepatosplenomegaly (p = 0.01), anemia (p = 0.02) and shorter jaundice to encephalopathy duration (p = 0.032) as compared to the ALF group, while higher transaminase levels (p = 0.03), bilirubin (p = 0.01), prothrombin time (p = 0.01), serum ammonia (p = 0.02) and mortality (p = 0.02) were observed in ALF patients. CONCLUSIONS: The most common cause for ALF was hepatitis A virus, followed by hepatitis B virus, while in ALF mimics it was malaria followed by dengue fever, in our study. Patients of ALF mimics can have similar presentation, but a high index of suspicion and awareness is required to identify the common infectious ALF mimics for early diagnosis.

Patients with autoimmune liver disease have glucose disturbances that mechanistically differ from steatotic liver disease.

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.

Long-term outcomes of patients with autoimmune hepatitis induced cirrhosis after immunosuppressive treatment.

INTRODUCTION: Autoimmune hepatitis is an immune-mediated liver disease that results in hepatic inflammation and subsequent fibrosis. We aimed to assess the natural history of autoimmune hepatitis in patients who had cirrhosis at the time of diagnosis. METHODS: We examined consecutive patients with autoimmune hepatitis (based on the revised International Autoimmune Hepatitis Group criteria) and cirrhosis who had long-term follow-up between 2012 and 2018. Complete clinical data, including longitudinal data, was obtained for each patient to determine clinical and biochemical outcomes. Decompensating events were defined as complications of portal hypertension. RESULTS: Thirty-four patients presenting with autoimmune hepatitis induced cirrhosis (age 50, 17-81; 71% women) were followed for an average of 8 years post-diagnosis. Fourteen (41%) patients had a decompensating event at diagnosis. All patients were begun on treatment; index decompensating events resolved in all patients. Twenty-six (76%) patients had normalization of transaminases; in this group, 4 (15%) patients developed one or more new decompensating events and 1 patient (4%) died. Of the 8 (24%) patients who did not have transaminase normalization, 6 (75%) developed one or more new decompensating events and 5 (62%) died or underwent liver transplant. There was a significant association between achieving normalization of transaminases and protection from developing a decompensating event ( P  = 0.003) and liver transplant or death ( P  = 0.001). CONCLUSION: Most patients with autoimmune hepatitis with cirrhosis at presentation achieved normalization of transaminases with treatment and rarely developed further decompensating events. We speculate that some of these patients had stabilization or reversal of portal hypertension.