Clinical Case Summary

Introduction: PBC is an autoimmune (AI) cholestatic disease characterized by destruction of small bile ducts leading to liver failure (LF).The pathogenesis is related to genetics, immunological and environmental factors, including viral infections such as CMV which is common in immunocompromised patients (HIV, chemotherapy, organ transplantation) but isn't typically associated with PBC in IC adults; this case may be the second one reported in the literature.
Case report: A 58 year old female patient with a history of type II diabetes presented with cholestatic jaundice, abdominal distension, fever, and asthenia. Physical examination revealed jaundice, grade II ascites, pruritus without hepatic encephalopathy. Ultrasound showed a heterogeneous liver + signs of portal hypertension (PH) and ascites. Blood tests revealed abnormal liver function with high cytolysis, cholestasis levels and LF. An etiological workup showed negative viral serologies (HAV, HBV, HCV, HEV) and positive SP100 antibodies. Histology was in favor of PBC at stage F4 cirrhosis. Hepatotropic viral tests (EBV, VZV, HSV, CMV) showed a positive IgG and IgM for CMV with high viral load.
An immunodeficiency screening was normal: negative HIV, C3 and C4 complement, normal levels of IgM IgG IgA.
The diagnosis was a reactivated CMV infection, revealing a previously asymptomatic PBC at stage F4 complicated by LF and PH with a severity CHILD score C10 MELD score 27.
Treatment with Ursodeoxycholic acid, diuretics, beta blockers, and intravenous Ganciclovir led to a favorable evolution of the viral load, cytolysis and cholestasis with persistent LF. The patient presented with type I hepatorenal syndrome and has been placed in liver transplant waiting list.
Conclusion: CMV infection with AI liver disease are rare in IC adults. When confronted with liver function disturbances and positive immunological tests, a viral etiology should be excluded before considering a dysimmune origin of the hepatopathy.

Clinical Case Summary

Defects in the PERCC1 gene have recently been identified as a cause of congenital diarrhoea and enteropathy with intestinal failure (IF) resulting from congenital enteroendocrine cell maldevelopment/dysfunction^1,2. Patients present within the first few weeks of life with watery diarrhoea and hyponatraemia and require long term parenteral nutrition (PN). No effective pharmacological treatments are available in these patients and health-care related quality of life is compromised by home PN and symptoms of malabsorptive diarrhoea. Here we report the first known functional characterization of enteric hormones in a 14-year-old patient (previously described as Patient A²) with IF due to a homozygous stop-gain point mutation in PERCC1. We observed widespread enteroendocrine hormone deficiency; specifically, negligible or undetectable fasting and post-prandial levels of gastrin, pancreatic polypeptide, ghrelin, PYY(1-36), PYY(3-36) and glucagon-like peptide-2 (GLP-2). At baseline, our patient was hyperphagic, passing 5-7 watery, steatorrhoeal stools per day and reliant on PN to provide 32% of his calculated weekly calorie requirement. Hormone replacement therapy with the GLP-2 analogue teduglutide resulted in prompt cessation of PN, resolution of hyperphagia, markedly improved weight gain and 10-fold reduction in fat malabsorption.
We report successful achievement of enteral autonomy in a patient with PERCC1-associated enteropathy and IF using the GLP-2 analogue teduglutide. These results have important implications for the pathogenesis and treatment of IF in patients with PERCC1-associated enteropathy and have therapeutic applicability to patients with enteroendocrine hormone deficiency from other congenital or acquired causes.

Article in press, Annals of Internal Medicine

References

1. Oz-Levi D, Olender T, Bar-Joseph I, et al. Noncoding deletions reveal a gene that is critical for intestinal function. Nature 2019;571:107-11.
2. Marek-Yagel D, Stenke E, Pode-Shakked B, et al. Nonsense mutation in the novel PERCC1 gene as a genetic cause of congenital diarrhea and enteropathy. Hum Genet 2023;142:691-6.

Introduction

With the implementation of the new nomenclature on steatotic liver disease (SLD), three main subgroups consisting of metabolic dysfunction-associated liver disease (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-related liver disease (ALD) have been defined. However, the risk of SLD for all-cause mortality and adverse outcomes as well as the different risks between MASLD, MetALD, and ALD needs further clarification.

Aims & Methods

Data from 13,599 participants without cancer of the population-based Gutenberg Health Study (baseline enrollment between 2007 and 2012) were cross-sectionally and prospectively analysed. The fatty liver index (FLI) with a score of ≥60 was used to define SLD. The subgroups of SLD (MASLD, MetALD, and ALD) were defined according to the new nomenclature based on five cardiometabolic criteria and alcohol consumption. The fibrosis-4 score (FIB-4) was calculated to determine patients at risk of fibrosis (≥1.3). All-cause mortality (10-year follow-up) and several adverse outcomes (hepatic decompensation, major adverse cardiac events (MACE), extrahepatic cancer) were analysed and compared across the subgroups of SLD. Cox regression models were used to estimate adjusted hazard ratios (aHR) and their 95% confidence intervals (CIs). Adjustments were made for age, sex, socioeconomic status, education, and smoking.

Results

The overall prevalence of SLD was 37.3% (n=5,074), whereas the prevalence of MASLD, MetALD, and ALD were 30.5% (n=4,154), 5.3% (n=717) and 1.5% (n=202), respectively. Almost half of the population were women (48.9%, n=6,644), and the mean age was 54.3 (±11.0) years. An elevated FIB-4 ≥1.3 was present in 20.2% (n=1,021) with SLD compared to 13.9% (n=1,184) without SLD (p<0.0001). The cumulative incidence of all-cause mortality was higher in SLD and all its subgroups MASLD, MetALD, and ALD compared to no SLD (p<0.0001). Stratification by FIB-4 ≥1.3 revealed a higher risk of all-cause mortality across all investigated SLD subgroups compared to FIB-4 <1.3 (p<0.0001). Each subgroup of SLD was associated with a higher risk of all-cause mortality: MASLD (aHR 1.6, 95% CI 1.4-1.9, p<0.0001), MetALD (aHR 1.6, 95% CI 1.3-2.1, p=0.00024) and ALD (aHR 1.6 95% CI 1.0-2.5, p=0.033). The risk of adverse outcomes was increased in MASLD (hepatic decompensation: aHR 1.2, 95% CI 1.0-1.5, p=0.0045; MACE: aHR 1.5, 95% CI 1.2-1.8, p<0.0001; extrahepatic cancer: aHR 1.2, 95% CI 1.1-1.4, p=0.0086), whereas no differences were seen for MetALD and ALD.

Conclusion

The prevalence of SLD and especially MASLD is high in the general population. Patients with SLD and any of its three main subgroups show a higher risk of all-cause mortality, whereas the risk for adverse outcomes is particularly increased in those with MASLD. These results highlight the importance of screening for SLD and related risk factors to improve outcomes.