Genetic Ancestry, Race, and Severity of Acutely Decompensated Cirrhosis in Latin America.

BACKGROUND & AIMS: Genetic ancestry or racial differences in health outcomes exist in diseases associated with systemic inflammation (eg, COVID-19). This study aimed to investigate the association of genetic ancestry and race with acute-on-chronic liver failure (ACLF), which is characterized by acute systemic inflammation, multi-organ failure, and high risk of short-term death. METHODS: This prospective cohort study analyzed a comprehensive set of data, including genetic ancestry and race among several others, in 1274 patients with acutely decompensated cirrhosis who were nonelectively admitted to 44 hospitals from 7 Latin American countries. RESULTS: Three hundred ninety-five patients (31.0%) had ACLF of any grade at enrollment. Patients with ACLF had a higher median percentage of Native American genetic ancestry and lower median percentage of European ancestry than patients without ACLF (22.6% vs 12.9% and 53.4% vs 59.6%, respectively). The median percentage of African genetic ancestry was low among patients with ACLF and among those without ACLF. In terms of race, a higher percentage of patients with ACLF than patients without ACLF were Native American and a lower percentage of patients with ACLF than patients without ACLF were European American or African American. In multivariable analyses that adjusted for differences in sociodemographic and clinical characteristics, the odds ratio for ACLF at enrollment was 1.08 (95% CI, 1.03-1.13) with Native American genetic ancestry and 2.57 (95% CI, 1.84-3.58) for Native American race vs European American race CONCLUSIONS: In a large cohort of Latin American patients with acutely decompensated cirrhosis, increasing percentages of Native American ancestry and Native American race were factors independently associated with ACLF at enrollment.

Vanishing bile duct syndrome related to DILI and Hodgkin lymphoma overlap: A rare and severe case.

Vanishing bile duct syndrome is a rare acquired condition, characterized by progressive loss of intrahepatic bile ducts leading to ductopenia and cholestasis. It can be associated with infections, ischemia, drug adverse reactions, neoplasms, autoimmune disease, and allograft rejection. Prognosis is variable and depends on the etiology of bile duct injury. We report the case of a 25-year-old female with cholestatic hepatitis and concomitant intakes of hepatotoxic substances, such as garcinia, field horsetail, and ketoprofen. On suspicion of a drug-induced liver injury, the drugs were promptly withdrawn and ursodeoxycholic acid was started with initial clinical and laboratory improvement, and the patient was discharged from the hospital. One month later, she had a new increase in bilirubin levels and canalicular enzymes, requiring a liver biopsy that showed significant loss of intrahepatic bile ducts, which was compatible with vanishing bile duct syndrome. This was confirmed by using cytokeratin 19 on immunohistochemistry. There was subsequent lymph node enlargement in several chains, and relevant weight loss. Histological analysis of a cervical lymph node revealed nodular sclerosis-subtype classic Hodgkin lymphoma. In this setting, vanishing bile duct syndrome was related to Hodgkin lymphoma and a drug-induced liver injury overlap, leading to progressive cholestasis with a worse prognosis. The patient's response to chemotherapy was poor, requiring biological therapy with brentuximab vedotin. It is crucial for physicians to create a broad differential diagnosis in suspected vanishing bile duct syndrome patients, especially to rule out malignancies.

Lysosomal Acid Lipase Deficiency Leading to Liver Cirrhosis: a Case Report of a Rare Variant Mutation.

Lysosomal acid lipase deficiency is a poorly diagnosed genetic disorder, leading to accumulation of cholesterol esters and triglycerides in the liver, with progression to chronic liver disease, dyslipidemia, and cardiovascular complications. Lack of awareness on diagnosis of this condition may hamper specific treatment, which consists on enzymatic replacement. It may prevent the progression of liver disease and its complications. We describe the case of a 53-year-old Brazilian man who was referred to our center due to the diagnosis of liver cirrhosis of unknown etiology. He was asymptomatic and had normal body mass index. He had dyslipidemia, and family history of myocardial infarction and stroke. Abdominal imaging tests showed liver cirrhosis features and the presence of intrahepatic calcifications. Initial investigation of the etiology of the liver disease was not elucidated, but liver biopsy showed microgoticular steatosis and cholesterol esters deposits in Kuppfer cells. The dosage of serum lysosomal acid lipase was undetectable and we found the presence of a rare homozygous mutation in the gene associated with the lysosomal acid lipase deficiency, (allele c.386A > G homozygous p.H129R).

Concordance of non-invasive mechanical and serum tests for liver fibrosis evaluation in chronic hepatitis C.

AIM: To determine the sensitivity and specificity of liver stiffness measurement (LSM) and serum markers (SM) for liver fibrosis evaluation in chronic hepatitis C. METHODS: Between 2012 and 2014, 81 consecutive hepatitis C virus (HCV) patients had METAVIR score from liver biopsy compared with concurrent results from LSM [transient elastography (TE) [FibroScan®/ARFI technology (Virtual Touch®)] and SM [FIB-4/aspartate aminotransferase-to-platelet ratio index (APRI)]. The diagnostic performance of these tests was assessed using receiver operating characteristic curves. The optimal cut-off levels of each test were chosen to define fibrosis stages F ≥ 2, F ≥ 3 and F = 4. The Kappa index set the concordance analysis. RESULTS: Fifty point six percent were female and the median age was 51 years (30-78). Fifty-six patients (70%) were treatment-naïve. The optimal cut-off values for predicting F ≥ 2 stage fibrosis assessed by TE were 6.6 kPa, for acoustic radiation force impulse (ARFI) 1.22 m/s, for APRI 0.75 and for FIB-4 1.47. For F ≥ 3 TE was 8.9 kPa, ARFI was 1.48 m/s, APRI was 0.75, and FIB-4 was 2. For F = 4, TE was 12.2 kPa, ARFI was 1.77 m/s, APRI was 1.46, and FIB-4 was 3.91. The APRI could not distinguish between F2 and F3, P = 0.92. The negative predictive value for F = 4 for TE and ARFI was 100%. Kappa index values for F ≥ 3 METAVIR score for TE, ARFI and FIB-4 were 0.687, 0.606 and 0.654, respectively. This demonstrates strong concordance between all three screening methods, and moderate to strong concordance between them and APRI (Kappa index = 0.507). CONCLUSION: Given the costs and accessibility of LSM methods, and the similarity with the outcomes of SM, we suggest that FIB-4 as well as TE and ARFI may be useful indicators of the degree of liver fibrosis. This is of particular importance to developing countries.

Mutações de resistência aos Inibidores de Protease em pacientes com Hepatite C crônica no Brasil / Resistance-associated variants to Hepatitis C virus Protease Inhibitors in naïve DAA patients in Brazil

A resistência viral aos inibidores de protease aparece rapidamente, pois essas cepas resistentes já existem naturalmente na população de quasispécies do vírus, emergindo como cepas mais prevalentes em relação às cepas selvagens quando o vírus sofre a pressão da droga. Esta seleção de cepas resistentes (RAVs) tem um papel im¬portante na falha terapêutica dessa classe de droga. Análise por sequenciamento direto em pacientes não tratados têm demonstrado diversas RAVs aos inibidores de protease (substituições nas posi¬ções V36, T54, V55, Q80, R155, D168 e V170). As mutações nas posições R155K e A156T da região NS3 estão associadas à alta resistência aos inibidores de protease. Dessa forma, os antivirais de ação direta (DAA) não podem ser utilizados em monoterapia. Aparentemente, existe uma diferença geográfica na distribuição dessas variantes de resistência. Nas populações europeia e america¬na, por exemplo, a variante de resistência na posição Q80K no ge¬nótipo 1a, que confere resistência ao simeprevir, foi encontrada em 25% a 35%. No entanto, na população brasileira uma frequência em torno de 1,8% de RAVs na posição Q80K, em três estudos, dois em VHC monoinfectados e outro em co-infectados VHC-HIV. O conhecimento da distribuição dos subgenótipos e do perfil de mutações nas diversas populações em todo o mundo vai se tornar importante na confecção de guidelines regionais, que seguramente terão suas particularidades de acordo com o perfil de cada região, no intuito de atingirmos máxima eficácia dos diferentes esquemas terapêuticos

Viral resistance to protease inhibitors appear quickly because these resistant strains occur naturally in the virus quasispecies population, emerging as the most prevalent strains compared to wild type strains when the virus is under drug pressure. This selection of resistant strains (RAVs) has an important role in therapeutic failure of this class of drug. Analyses by direct sequencing in untreated patients have shown various RAVs to protease inhibitors (substitutions at positions V36, T54, V55, Q80, R155, A156, D168 and V170). Mutations at positions R155K and A156T on NS3 region are associated with high resistance to protease inhibitors. Thus, the direct action antivirals (DAA) may not be used as monotherapy. Apparently, there is a geographical difference in the distribution of these variants of resistance worldwide. In European and American HCV population for example, resistance variants in the position Q80K genotype 1a, which confers resistance to simeprevir was found in 25% to 35% of patients. However, in the Brazilian population the Q80K mutation was found at a frequency of around 1.8%, in three studies, two in HCV monoinfected and another in coinfected HIV-HCV patients. The distribution of this mutation profile in different populations around the world will become important in the preparation of regional guidelines, which surely will have their particularities according to the HCV subtyping distribution and mutation profile of each region in order to achieve maximum effectiveness of different treatment regimens

S-nitroso-N-acetylcysteine attenuates liver fibrosis in experimental nonalcoholic steatohepatitis.

S-Nitroso-N-acetylcysteine (SNAC) is a water soluble primary S-nitrosothiol capable of transferring and releasing nitric oxide and inducing several biochemical activities, including modulation of hepatic stellate cell activation. In this study, we evaluated the antifibrotic activity of SNAC in an animal model of nonalcoholic steatohepatitis (NASH) induced in Sprague-Dawley rats fed with a choline-deficient, high trans fat diet and exposed to diethylnitrosamine for 8 weeks. The rats were divided into three groups: SNAC, which received oral SNAC solution daily; NASH, which received the vehicle; and control, which received standard diet and vehicle. Genes related to fibrosis (matrix metalloproteinases [MMP]-13, -9, and -2), transforming growth factor ß-1 [TGFß-1], collagen-1α, and tissue inhibitors of metalloproteinase [TIMP-1 and -2] and oxidative stress (heat-shock proteins [HSP]-60 and -90) were evaluated. SNAC led to a 34.4% reduction in the collagen occupied area associated with upregulation of MMP-13 and -9 and downregulation of HSP-60, TIMP-2, TGFß-1, and collagen-1α. These results indicate that oral SNAC administration may represent a potential antifibrotic treatment for NASH.

Pro- and anti-inflammatory cytokines in steatosis and steatohepatitis.

BACKGROUND: Fatty liver disease is a problem in both bariatric patients and in patients with moderate obesity. Tumor necrosis factor (TNF)-alpha has been frequently measured in nonalcoholic steatohepatitis (NASH) with or without diabetes, but less is known about interleukin (IL)-6 and IL-10. METHODS: Moderately obese patients (n = 80) with histologically proven steatosis (n = 29) and NASH (n = 51) were recruited. Serum levels of cytokines were documented along with clinical information. The aim was to identify the correlates of such biomolecules in a stable population. RESULTS: Diabetes tended to be more associated with NASH (52.5% instead of 41.4%, P = 0.015), with no difference of age, gender, or body mass index regarding steatosis. For the entire population, cytokine changes were not significant, including TNF-alpha and IL-6. In diabetics only, all markers tended to diminish with NASH, especially IL-10 (P = 0.000). IL-10 correlated with homeostatic model assessment index (P = 0.000) and other variables of glucose homeostasis in diabetes, thus representing a major marker of the disease. CONCLUSIONS: (1) Generally inconsistent changes in pro- and anti-inflammatory cytokines occurred when NASH was globally compared to steatosis. (2) In contrast, downregulation of IL-6 and IL-10 was perceived in diabetics with NASH. (3) Arterial hypertension did not play a role in these circumstances. (4) IL-10 maintained strong correlations with glucose metabolism indices. (5) TNF-alpha could not be incriminated for progressive liver damage, as values failed to increase in NASH. (6) Investigations of IL-10 and other counterregulatory cytokines are lacking in this context and deserve further studies.

Primitive reflexes and cognitive function.

BACKGROUND: Data on the prevalence of primitive reflexes (PR) in adulthood, their pathological significance and relationship to age and cognition are controversial. OBJECTIVE: To study the relationship between PR and cognition in 30 patients with probable Alzheimer's disease (AD) and 154 control subjects. METHOD: Diagnosis of probable AD was based on DSM-IV, NINCDS-ADRDA, and CAMDEX criteria. Primitive reflexes were quantified from zero (absent) to 1 (mild) or 2 (markedly present). The Cognitive Abilities Screening Instrument-Short Form (CASI-S) was used to evaluate registration, temporal orientation, verbal fluency and recall. A drawing test was added. RESULTS: Most frequent PR among demented and controls were suck (77% and 62%, respectively) and snout (60% and 27%), followed by glabellar (30% and 19%), paratonia (37% and 5%), and palmomental (23% and 5%). None of controls had more than three PR. Frequency of PR tended to increase with age and cognitive deterioration. Grasp and Babinski responses were found only in dementia patients. Primitive reflexes were not correlated with each other, except snout with suck, and snout with glabellar reflex. CONCLUSION: The finding of grasp and Babinski sign, or the presence of more than three primitive signs, particularly the combination of paratonia, snout, suck, and palmomental reflexes strongly suggests brain dysfunction, especially when these signs are marked and accompanied by deficits in orientation, recall, verbal fluency, and constructional praxis.

Primitive reflexes and cognitive function

CONTEXTO: A prevalência e significado patológico dos reflexos primitivos (RP) no adulto, bem como sua relação com a idade e a cognição, são questões controversas. OBJETIVO: Estudar a relação entre RP e cognição em 30 pacientes com doença de Alzheimer (DA) e 154 sujeitos controles normais. MÉTODO: O diagnóstico de DA baseou-se nos critérios DSM-IV, NINCDS-ADRDA e CAMDEX. Os RP foram quantificados de 0 (ausente) a 1 (leve) ou 2 (acentuado). CASI-S (Cognitive Abilities Screening Instrument -Short Form) foi usado para avaliar o registro, orientação temporal, fluência verbal e evocação. Um teste de cópia de pentágonos foi acrescentado. RESULTADOS: Os RP mais frequentes nos pacientes e controles foram o de sucção (77% e 62%, respectivamente) e "snout" (60% e 27%), seguidos do glabelar (30% e 19%), paratonia (37% e 5%) e palmomentoniano (23% e 5%). Nenhum sujeito controle teve mais que três RP. A frequência dos RP tendeu a aumentar com a idade e a deterioração cognitiva. O reflexo de preensão e o sinal de Babinski foram encontrados apenas nos pacientes com DA. Os RP não se correlacionaram uns com os outros, exceto o reflexo "snout" com o de sucção e com o glabelar.CONCLUSÃO: O achado de reflexo de preensão e sinal de Babinski, ou a presença de mais de três sinais primitivos, particularmente a combinação de paratonia e reflexos "snout", sucção e palmomentoniano, são sugestivos de disfunção cerebral, especialmente quando esses sinais são acentuados e acompanhados de déficits de orientação, evocação, fluência verbal e praxia construcional.

[Validation of the Brazilian version of mini-test CASI-S].

OBJECTIVE: To determine CASI-S accuracy in the diagnosis of dementia. METHOD: The Cognitive Abilities Screening Instrument - Short Form (CASI-S) was applied in 43 Alzheimer's disease (AD) patients and 74 normal controls. AD diagnosis was based on DSM-IV, NINCDS-ADRDA, and CAMDEX. CASI-S includes: registration, temporal orientation, verbal fluency (4-legged animals in 30s), and recall (3 words). Its maximum score is 33 points. A copy of 2 pentagons was added. RESULTS: ROC curve showed an accuracy of 0.87, with standard error of 0.032, and 95% confidence intervall between 0.795 and 0.925. The cut-off score for cognitive deficit was 23, with sensitivity of 76.7%, specificity 86.5%, positive likelihood ratio (LR) 5.68, and negative LR 0.27. The cut-off score for subjects 70 years or older was 20, with sensitivity of 71.4% and specificity 97.1%. CONCLUSION: CASI-S is a practical test, with high specificity, particularly in individuals above 70 years of age. The adding of the drawing test did not improve its accuracy.

Validation of the Brazilian version of mini-test CASI-S

OBJETIVO: Determinar a acurácia do CASI-S no diagnóstico de demência. MÉTODO: O CASI-S (Cognitive Abilities Screening Instrument - Short Form) foi aplicado em 43 pacientes com doença de Alzheimer (DA) e 74 controles normais. O diagnóstico de DA baseou-se no DSM-IV, NINCDS-ADRDA e CAMDEX. O CASI-S inclui: registro, orientação temporal, fluência verbal (animais quadrúpedes em 30s), e evocação (3 palavras). O escore máximo é 33 pontos. Foi adicionado um teste de cópia de 2 pentágonos. RESULTADOS: A curva ROC mostrou acurácia de 0,87, com erro padrão de 0,032, e intervalo de confiança de 95% entre 0,795 e 0,925. O ponto de corte para déficit cognitivo foi 23 pontos, com sensibilidade de 76,7%, especificidade de 86,5%, valor preditivo (VP) positivo de 5,68, e VP negativo de 0,27. Para sujeitos com 70 anos ou mais, o ponto de corte foi 20, com sensibilidade de 71,4% e especificidade de 97,1%. CONCLUSION: O CASI-S é um teste prático, com alta especificidade, particularmente em indivíduos com idade acima de 70 anos. O teste de cópia dos pentágonos não melhorou sua acurácia.