Autoimmune Hepatitis: Safety of Low Dose Steroids and Utility of Aminotransferases

K Manwani et al. JPGN 2022; 75: 252-256. Long-Term Growth in Children and Young People with Autoimmune Liver Disease Treated with Daily Steroids

This retrospective study of patients (n=74) diagnosed with autoimmune hepatitis (AH) prior to 16 years of age examined the safety of low dose steroids. Median age of patients with 12.8 yrs and median followup was 12.6 years. Typically, after induction, patients were tapered over ~2 months to 5 mg per day (& 2.5 mg per day if <12 years). Key findings:

  • Growth of patients with AILD on a daily maintenance dose of steroids remains stable and within normal range during long-term follow up.  At all time-points, the mean z-scores for weight, height and BMI were within the normal range, indicating normal nutritional status. 
  • Small, daily doses are effective in maintaining disease control and minimize the need for high-dose steroid pulses during relapses.
  • In this cohort, there were 14 patients in which prednisolone was utilized as monotherapy; the majority received cotherapy with azathioprine (n=44), mycophenolate (n=12); triple-therapy was utilized tacrolimus (n=4).
  • Prednisolone was stopped in 17 patients (23%) after a median time of 9.5 years (range 3 years-14 years)

M Biewenga et al. Clin Gastroenterol Hepatol 2022; 20: 1776-1783. Open access! Aminotransferases During Treatment Predict Long-Term Survival in Patients With Autoimmune Hepatitis Type 1: A Landmark Analysis

In this multicenter cohort study (n=301), it was shown that higher aminotransferases during treatment were independent of baseline risk factors associated with liver transplantation–free survival in patients with AIH type 1. Median followup was 99 months. Key finding:

  • During follow-up, 15 patients required liver transplantation and 33 patients died
  • In multivariate analysis AST at 12 months (HR, 2.13; P < .001) was predictive for survival independent of age, AST at diagnosis and cirrhosis, while IgG was not associated with survival (HR, 1.30; P = .53)
  • There was a trend toward a worse survival in patients with mildly elevated aminotransferases (1–1.5× upper limit of normal) compared with patients with normal aminotransferases (P = .097)

My take: Normalization of AST (aminotransferases), especially during the first year of treatment, is associated with better long-term outcomes. The study by Manwani et al suggest that long-term low dose steroids are associated with low risks.

Also: Y Li et al.Hepatology 2022; 76: 564-575. Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1 This study with 1622 Chinese patients identified two novel loci (CD28/CTLA4/ICOS and SYNPR) and may provide potential targets for additional treatments.

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AST Values and Cumulative Live Transplant-Free Survival

Liver Shorts: Biliary Atresia Organoids, AIH Pregnancy Outcomes, ALT Levels in Primary Care, Polyreactive IgG for AIH

SP Amarachintha et al. Hepatology 2022; 75: 89-103. Open Access: Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia

This is a super cool article documenting a new human model for studying biliary atresia. The authors “generated biliary organoids from liver biopsies of infants with biliary atresia and normal and diseased controls…Organoids from biliary atresia are viable and have evidence of halted epithelial development. The induction of developmental markers, improved cell-cell junction, and decreased epithelial permeability by EGF and FGF2 identifies potential strategies to promote epithelial maturation and function.”

The authors note that delayed development of cholangiocytes impair barrier function and leave the liver susceptible to various insults which can trigger an inflammatory response with potential progression to obliteration of the bile ducts.

CW Wang et al. Hepatology 2022; 75: 5-12. Open Access: Outcomes of pregnancy in autoimmune hepatitis: A population-based study

Among 18,595,345 pregnancies, 935 (<0.001%) had AIH (60 with cirrhosis) and 120,100 (0.006%) had other CLD (845 with cirrhosis). Key findings:

  • AIH was not associated with postpartum hemorrhage, maternal, or perinatal death
  • AIH was associated with preterm births when compared with women without CLD (OR: 2.0)
  • The odds of gestational diabetes (GDM) and hypertensive complications (pre-eclampsia, eclampsia, or hemolysis, elevated liver enzymes, low platelets) were significantly higher in AIH compared to other CLD (GDM: OR 2.2 and hypertensive complications: OR: 1.8) and also compared to no CLD in pregnancy (GDM: OR: 2.4 and  hypertensive complications: OR: 2.4)

SJ Wu et al. J Pediatr 2022; 240: 280-283. The Prevalence of Elevated Alanine Aminotransferase Levels Meeting Clinical Action Thresholds in Children with Obesity in Primary Care Practice

In this brief report, the authors identified 7.8% of children from a cross-sectional California cohort (n=12,945) with ALT >44 U/L and BMI in the 95% or higher (2012-2014). Males were twice as likely to have elevated ALT. Ethnicity rates were higher in hispanics, asians than white and black children (in males: 12%, 10.4%, 7.3% and 3.1%, respectively)

R Taubert et al. Hepatology 2022; 75: 13-27. Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis

Key findings: Polyreactive IgGs (pIgGs) are a common finding in untreated AIH and have “the highest overall accuracy for the distinction between AIH and non-AIH LD compared to the most common conventional autoantibodies.” In addition, in this study with 1568 adutls, pIgGs were present in “up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD.”

Autoantibodies Significance in Pediatric Fatty Liver Disease

A Khayat, B Vitola et al. J Pediatr 2021; 239: 155-160. Prevalence and Clinical Significance of Autoantibodies in Children with Overweight and Obesity with Nonalcoholic Fatty Liver Disease

When investigating elevated liver enzymes in teenagers, serology for autoimmune hepatitis (AIH) is frequently obtained. In the face of overweight/obesity, the majority will have nonalcoholic fatty liver disease (NAFL). How many with elevated autoantibodies actually have autoimmune liver disease (ALD)? Some information regarding this issue is available in the article by Khayat et al.

Methods: A retrospective, cross-sectional study of 181 children with a biopsy-proven diagnosis of NAFL, NASH, autoimmune hepatitis (AIH), or primary sclerosing cholangitis (PSC) and a body mass index (BMI) >85th percentile treated between 2007 and 2016.

Key findings:

  • Antinuclear antibody (ANA), anti-actin antibody, and anti–liver kidney microsomal (LKM) antibody were positive in 16.1%, 13.8%, and 0%, respectively, of the patients with NAFL and in 32.8%, 15.5%, and 0%, respectively, of those with NASH
  • Total immunoglobulin G (IgG) was elevated in 27.3% of the patients with NAFL and in 47.7% of those with NASH, but in 100% of those with ALD. A normal IgG level was the “strongest negative predictor of ALD, followed by a negative ANA and actin.”
  • The positive predictive value of LKM was 100% for ALD but only 29% for ANA and 46% for anti-actin antibody. ANA positivity in this cohort was associated with more insulin resistance
  • ALD was present in 29/181 (16%).  12 (6.6%) with isolated ALD (AIH, PSC, or overlap), and 17 (9.4%) with combined ALD and NAFLD
  • BMI >98% “appears to be an important breakpoint above which ALD is less likely” even when IgG is high with a positive ANA
  • Limitations: Retrospective study, not every patient had all of the ALD serology tests

My take: Even heavy kids may have autoimmune liver disease. In those with abnormal serology, about 1 in 6 will have ALD, either in combination with NAFL or as the sole etiology of abnormal LFTs.

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Changes in Latitudes and Changes in Autoimmune Liver Disease

GJ Webb et al. Clin Gastroenterol Hepatol 2021; 19: 2587-2596. Open Access: The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude

Methods: A retrospective cohort study using anonymized UK primary care records (2002-2016). All adults without a baseline diagnosis of AILD (autoimmune liver disease) were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database.

AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis

Key findings:

  • 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34–2.60); PSC, 0.74 (95% CI, 0.67–0.82); and AIH, 1.94 (95% CI, 1.83–2.06) per 100,000 per year.
  • A more northerly latitude was associated strongly with incidence of PBC: 2.16 to 4.86 from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 to 3.28 (P = .003), but not incidence of PSC: 0.82 to 1.02 (P = .473)
  • After adjustments, PBC was more frequent in smokers than those who had never smoked at 3.40 (3.03–3.77) per 100,000/y and 1.96 (1.80–2.12) cases per 100,000/y; there was a lower incidence of PSC in smokers 0.47 (0.33–0.61) per 100,000/y compared with those who had never smoked 0.95 (0.83–1.07) per 100,000/y. For AIH, there was no difference between current smokers and those who had never smoked

The authors speculate in the discussion about potential reasons why latitude could correlate with disease incidence. Some potential explanations include sunlight/vitamin D metabolism (though this is at odds with the fact that those with increased skin pigmentation are NOT at increased risk), environmental exposures (related to geology, diet, air quality) or unrecognized genetic tendency based on geography.

My take: In the UK, there is an association between a more northernly latitude and both PBC and AIH.

Related blog post: Aspen Webinar 2021 Part 5 -Autoimmune Liver Disease & PSC

Figure 2

Mortality Risk With Autoimmune Hepatitis

R Sharma et al. Clin Gastroenterol Hepatol 2021; 19: 2636-2647. Open Access PDF: Increased Mortality Risk in Autoimmune Hepatitis: A Nationwide Population-Based Cohort Study With Histopathology

In this nationwide population-based cohort study in Sweden from 1969-2017 of 6,016
adults with histologically-confirmed AIH (all 18 years or older) and 28,146 matched general population, key findings:

  • 3,185 individuals with AIH died (41.4/1000 person-years) compared with 10,477 reference individuals (21.9/1000 person-years)
  • The 10-year cumulative incidence of death was 32.3% (95%CI [ 31.1-33.6) for AIH individuals and 14.1% (95%CI [ 13.7-14.5) for reference individuals
  • AIH individuals with cirrhosis on biopsy had a high risk of death (HR [ 4.55; 95%CI [ 3.95-5.25), while mortality risks for patients with noncirrhotic fibrosis (HR, 2.68) and inflammation without fibrosis (HR, 2.18) were similar to overall risk
  • In this cohort, 13.7% had cirrhosis at diagnosis (lower than other studies)

My take: In this study over nearly 50 years, AIH was associated with “a 2-fold increased risk of death. Risks were particularly high in individuals with cirrhosis, portal hypertension (HR, 7.55), and overlap with cholestatic liver disease.”

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Why It Is Hard to Stop Immunosuppression with Autoimmune Hepatitis and Lower Bone Density with Fatty Livers

C Schulthei et al. Hepatology 2021; 73: 1436-1448. Full text: Next-Generation Immunosequencing Reveals Pathological T-Cell Architecture in Autoimmune Hepatitis

This is highly technical study of 60 patients with AIH. “Our key finding was a clearly biased signature of TRBV-J gene usage in peripheral and liver-infiltrating T-cells of patients with AIH, independent of AIH predisposing HLA-DRB1 alleles. This signature was unaffected by immunosuppressive treatment and not related to complete biochemical disease remission. This suggests that treatment acted on T-cell functionality rather than on the underlying pathological T-cell architecture in this disease that has a high relapse rate.”

My take (borrowed from authors): “Patients with AIH show profound and persisting T-cell architectural changes that may explain high relapse rates after tapering immunosuppression.”

Related blog posts:

LF Chun et al. J Pediatr 2021; 233: 105-111. Hepatic Steatosis is Negatively Associated with Bone Mineral Density in Children

Key findings:

  • Using a community-based sample of 235 children, the authors found that there was a significant negative relationship between liver MRI-PDFF and BMD z score R = −0.421, P < .001).
  • There was no significant association between vitamin D status and BMD z score (P = .94).
  • Children with clinically low BMD z scores were found to have higher alanine aminotransferase (P < .05) and gamma-glutamyl transferase (P < .05) levels compared with children with normal BMD z scores.

My take: This study shows another organ that is affected in children with fatty liver disease; other associated problems include increased risk for cardiovascular disorders, pancreatic dysfunction/diabetes, cancer, polycystic ovary syndrome, and neurologic disorders

Related blog posts:

Image below near the Seven Mile Road on the Florida Keys:

Trends in Liver Diseases: Autoimmune Liver Diseases and Fatty Liver

1st Study: M Lamba et al. Clin Gastroenterol Hepatol 2021; 19: 573-579. Full text: Trends in Incidence of Autoimmune Liver Diseases and Increasing Incidence of Autoimmune Hepatitis

This was a population-based prospective study from Canterbury, New Zealand

Key findings:

  • Overall incidence rates were 1.93 per 100,000 for AIH (95% CI, 1.58–2.34), 0.51 per 100,000 for PBC (95% CI, 0.33–0.73), and 0.92 per 100,000 for PSC (95% CI, 0.68–1.21). 
  •  The incidence rate of AIH was significantly higher during the period of 2014–2016 (2.39 per 100,000; 95% CI, 1.76–3.23) than during the period of 2008–2010 (1.37 per 100,000; 95% CI, 0.91– 2.06) (P < .05). Incidences of PBC and PSC did not change significantly.
  • In 2016, prevalence values were 27.4 per 100,000 for AIH (95% CI, 23.58–32.0), 9.33 per 100,000 for PBC (95% CI, 7.13–12.05), and 13.17 per 100,000 for PSC (95% CI, 10.56–16.42).

My take: This study indicates that autoimmune hepatitis has been increasing in incidence.

Related blog posts:

2ndStudy: ZM Younossi et al. Clin Gastroenterol Hepatol 2021; 19: 580-589. Full text: Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States

This study was an analysis of data from the Scientific Registry of Transplant Recipients (2002 through 2019).

Key findings:

  • In 2002, the most common etiologies of non-acute liver failure on the liver transplant waitlist (in patients without HCC)
  • In 2019, among patients without HCC, NASH was the second leading indication for liver transplantation (28% of patients), after ALD (38% of patients). were chronic HCV infection (37%) and ALD (16%), whereas only 5% had NASH
  • HCC accounted for 27,799 patients (16.5%) and was commonly due to chronic HCV throughout study period

My take: Demand for liver transplantation has NOT improved despite curative therapy for chronic hepatitis C. This is due to increased liver failure related to fatty liver disease and alcoholic liver disease.

Related blog posts:

Figure 1 Prevalence of the most common CLD etiologies in waitlisted liver transplant candidates without HCC. (A) Proportion of all non-HCC listings with known etiology; (B) the proportion relative to that seen in 2002.

Predicting Outcomes in Childhood Autoimmune Hepatitis

G Porta et al. J Pediatr 2021; 229: 95-101. Autoimmune Hepatitis: Predictors of Native Liver Survival in Children and Adolescents

This retrospective study enrolled a total of 819 patients, 89.6% with AIH-1 and 10.4% with AIH-2

Key findings:

  • The overall survival was 93.0%, with a native liver survival (NLS) of 89.9%; 4.6% underwent liver transplantation
  • The risk of death or liver transplantation during follow-up was 3.2 times greater in patients with AIH-1 ( P = .024). 
  • Normal C3 levels was associated with longer NLS ( P = .017). The chance of death or liver transplantation during follow-up was 3.4 times greater in patients with C3 level below normal
  • Death or liver transplantation during follow-up was 2.8 times greater in patients with associated sclerosing cholangitis ( P = .046).

My take: This large cohort from Brazil shows that a significant portion of children with AIH do NOT do well, especially if they have associated sclerosing cholangitis.

Related blog posts:

Liver Shorts -February 2021 (part 2)

M Biewenga et al. Liver Transplantation 2020; 26: 1573-1581. Full text: Early Predictors of Short-Term Prognosis in Acute and Acute Severe Autoimmune Hepatitis

Key points:

  •  After the start of immunosuppressive therapy, bilirubin, albumin, and INR normalized in 70%, 77%, and 69%, respectively, in a median of 2.6 months, 3 months, and 4 weeks, respectively, in patients with A-AIH and AS-AIH
  • Deterioration of liver function (bilirubin, INR) after 2 weeks of treatment should lead to rapid evaluation for LT and consideration of second-line medication.

I Ziogas et al. J Pediatr 2021; 228: 177-182. Mortality Determinants in Children with Biliary Atresia Awaiting Liver Transplantation

Key points:

  • The cumulative incidence of waitlist mortality was 5.2%. Median waitlist time was 83 days.
  • In multivariable analysis (n = 2253), increasing bilirubin level ( P < .001), portal vein thrombosis ( P = .03), and ventilator dependence ( P < .001) at listing were associated with a higher risk, whereas weight ≥10 kg at listing ( P = .009) was associated with a lower risk of waitlist mortality. 

References Only:

HM DuBrokc, MJ Krowka. Hepatology 2020; 1455-1460. The Myths and Realities of Portopulmonary Hypertension

Related blog posts:

H Oh et al. Clin Gastroenterol Hepatol 2020; 18: 2793-2802. Full text: No Difference in Incidence of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Virus Infection Treated With Entecavir vs Tenofovir Related blog post: Is Tenofovir the Best Medication for HBV?

Evanston, IL

Autoimmune Hepatitis -Early Response Associated with Remission

Briefly noted: S Pape et al .Clin Gastroenterol Hepatol 2020; 18: 1609-1617. Full Text: Rapid Response to Treatment of Autoimmune Hepatitis Associated With Remission at 6 and 12 Months

Methods: This was a retrospective cohort study, collecting data from 2 independent cohorts of adults (each with n=370) with AIH from 12 centers in 7 countries in Europe.

Key findings:

  • The authors found that a significant decrease in level of AST after 8 weeks of treatment was significantly associated with normalization of transaminase levels at 26 and 52 weeks (P < .001)
  • In both cohorts, rapid responders (≥80% decrease in level of AST after 8 weeks) were more likely to achieve normalization of transaminases at 26 and 52 weeks when compared to non-rapid responders
  • Rapid responders in the discovery cohort had lower risk of liver-related death or transplantation (adjusted hazard ratio 0.18)
  • Slow responders (without normalization of transaminases after 1 year) had the highest risk of liver transplantation or liver-related death.

My take: It is no surprise that patients who respond rapidly to treatment would fare better.  This study establishes a target of >80% improvement in AST at 8 weeks.

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