Pathogenesis of hypothyroidism-induced NAFLD: Evidence for a distinct disease entity?

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, may be associated with primary hypothyroidism. However, the pathogenesis underlying such an association is complex and not completely understood. Here, we specifically discuss the pathogenic mechanisms potentially involved in hypothyroidism-induced NAFLD. To this end, we summarize the general pathophysiology of thyroid hormones (TH). Next, we analyze the published data from rodent studies by discussing whether hypothyroid rats may develop NAFLD via hyperphagia; whether mitochondria become energetically more efficient; what the overall energy balance is and if diversion of fatty substrates occurs; and the latest advancements in molecular pathogenesis brought about by metabolomics, cell imaging, lipophagy, autophagy and genetically engineered mouse models. Moreover, we discuss the data published regarding humans on the pathogenic role of TH, metabolic syndrome and other risk factors in hypothyroidism-related NAFLD as well as the putative mechanisms underlying the development of NAFLD-related hepatocellular carcinoma in hypothyroidism. In conclusion, although many research questions still remain unanswered, the pathophysiology of hypothyroidism-induced NAFLD makes this a potentially curable and distinct disease entity. However, further studies are needed to better elucidate the underlying mechanisms, and to ascertain whether treatment with either TH or thyromimetic agents improves NAFLD.     

Is diabetic cardiomyopathy a specific entity?

Diabetes mellitus(DM) is characterised by hyperglycemia, insulin resistance and metabolic dysregulation leading to diastolic and systolic dysfunction in diabetes. In this review, the pathogenetic and pathomorphological changes leading to diastolic and systolic dysfunction in diabetes are discussed. Changes in metabolic signalling pathways, mediators and effectors contribute to the pathogenesis of cardiac dysfunction in DM called diabetic cardiomyopathy(DC). Echocardiographic studies report on the association between DM and the presence of cardiac hypertrophy and myocardial stiffness that lead to diastolic dysfunction. More recently reported echocardiographic studies with more sensitive techniques, such as strain analysis, also observed systolic dysfunction as an early marker of DC. Depression of systolic and diastolic function is continuum and the line of separation is artificial. To conclude, according to current knowledge, DC is expected to be a common single phenotype that is caused by different pathogenetic and pathomorphological changes leading to diastolic and systolic dysfunction in diabetes.     

Neurogenic appendicopathy: a clinical disease entity?

BACKGROUND AND AIMS: This study compared two histopathological examinations for the diagnosis of neurogenic appendicopathy (NA), assessed the frequency of NA, and evaluated whether it is a clinical disease entity distinct from acute appendicitis. PATIENTS AND METHODS: In a prospective observational multicenter study (surgical departments of five hospitals with one reference pathology) we evaluated 282 patients who underwent appendectomy for suspected appendicitis; we examined the frequency of NA in acute appendicitis and in the negative appendectomy group. For the diagnosis two staining methods were compared. We also attempted to determine clinical features of NA. RESULTS: We observed 93% accuracy for hematoxylin-eosin staining compared with S-100 staining (reference standard) in the diagnosis of NA. There was NA in 3.8% of patients with acute appendicitis and in 47% of those with negative appendectomy. We observed significant differences between the three groups (NA without appendicitis, acute appendicitis, and negative appendectomy without neurogenic appendicopathy) only for sex, age, vomiting, similar previous complaints, rebound tenderness, guarding, rigidity, leukocytes (univariate analysis) and sex (multivariate analysis). CONCLUSION: Neurogenic appendicopathy is a histopathological entity that can be identified by hematoxylin-eosin staining. History and clinical examination do not enable us preoperatively to differentiate between acute appendicitis, NA, and negative appendectomy.     

Inflammatory bowel disease of primary sclerosing cholangitis: A distinct entity?

This is a review of the characteristic findings of inflammatory bowel disease(IBD)associated with primary sclerosing cholangitis(PSC)and their usefulness in the diagnosis of sclerosing cholangitis.PSC is a chronic inflammatory disease characterized by idiopathic fibrous obstruction and is frequently associated with IBD.IBDassociated with PSC(PSC-IBD)shows an increased incidence of pancolitis,mild symptoms,and colorectal malignancy.Although an increased incidence of pancolitis is a characteristic finding,some cases are endoscopically diagnosed as right-sided ulcerative colitis.Pathological studies have revealed that inflammation occurs more frequently in the right colon than the left colon.The frequency of rectal sparing and backwash ileitis should be investigated in a future study based on the same definition.The cholangiographic findings of immunoglobulin G4-related sclerosing cholangitis(IgG4-SC)are similar to those of PSC.The rare association between IBD and IgG4-SC and the unique characteristics of PSC-IBD are useful findings for distinguishing PSC from IgG4-SC.     

Risk of cardiovascular disease and chronic kidney disease in diabetic patients with non-alcoholic fatty liver disease: just a coincidence?

Non-alcoholic fatty liver disease (NAFLD) is estimated to afflict ~20-30% of the general population, and over 70% of the patients with Type 2 diabetes. Given the expected rise in the prevalence of obesity and diabetes, NAFLD will be, if not already there, an epidemic. The consequences of NAFLD are numerous, and range from progression to chronic liver disease with its associated morbidity and mortality, to worsening insulin resistance and Type 2 diabetes, to being a contributor to both cardiovascular disease (CVD) and chronic kidney disease (CKD). NAFLD is, therefore, a complex problem with implications far beyond the liver. This review focuses on the rapidly expanding body of clinical evidence suggesting that NAFLD is associated with an increased prevalence and incidence of both CVD and CKD in patients with diabetes. This association appears to be independent of obesity, hypertension, and other potential confounding factors. However, given the heterogeneity and small number of observational studies, further research is urgently required to corroborate the prognostic role of NAFLD in the development and progression of CVD and CKD among patients with diabetes, and to further elucidate the complex and intertwined mechanisms that link NAFLD with these adverse outcomes.     

Chronic basophilic leukemia: a distinct clinico‐pathologic entity?

OBJECTIVE: We sought to better define a group of rare and poorly understood myeloproliferative disorders that are characterized by prominent chronic basophilia in the absence of the Philadelphia chromosome (Ph) or its molecular equivalent. METHODS: We screened our institution's electronic database from 1975 onwards, and identified four such cases. Clinical data and bone marrow pathology were carefully reviewed for these patients. RESULTS: Two patients had prominent manifestations of basophil mediator-release and another presented with pituitary dysfunction. Bone marrow examination uniformly revealed trilineage hyperplasia with basophilia and eosinophilia, dysplastic megakaryocytic hyperplasia, and the absence of megakaryocyte clustering. An abnormal pattern of atypical mast cells was noted in two cases. While disease palliation was effectively achieved with hydroxyurea for one patient, transformation to acute myeloid leukemia was eventually observed in this case. Another patient has achieved long-term disease-free survival after undergoing allogeneic stem cell transplantation. CONCLUSIONS: Our observations reveal a striking pathologic similarity among all four cases, and suggest this disease, which may be aggressive with the potential to transform into acute leukemia, to possibly represent a distinct clinico-pathologic entity (chronic basophilic leukemia).     

Where does albuminuria come from in diabetic kidney disease?

The classic mechanism to explain albumin excretion in diabetes has been permeability defects in the glomerular filter. However, a new concept has emerged that albuminuria can be explained by the two major pathways the proximal tubular cell uses to process filtered albumin. Specifically, albumin permeability through the glomerular filter is only governed by size selectivity. Most of the filtered albumin is retrieved by the proximal tubular cell and returned to the peritubular blood supply. Albuminuria in the nephrotic range would arise from retrieval pathway dysfunction. The small quantities of filtered albumin that are not retrieved undergo obligatory lysosomal degradation before urinary excretion as small peptide fragments. This pathway is sensitive to metabolic factors responsible for hypertrophy and fibrosis, particularly molecules such as angiotensin II and transforming growth factor-β1, whose production is stimulated by hyperglycemic environments. Dysfunction in this degradation pathway may lead to albuminuria below the nephrotic range.     

Is heart failure in African Americans a distinct entity?

Heart failure remains a major health problem in the United States and is particularly problematic in the African American community where the disease exhibits excessive morbidity and mortality. Hypertension is a predominant etiology for heart failure among African Americans with an aggressive incidence of end-organ damage. Despite the advances in treatment of heart failure with neurohormonal attenuation, there appears to be inconsistency in the response of African Americans compared to Caucasians. This discordance with regard to response to treatment and etiology of heart failure between African Americans and Caucasians begets the question whether heart failure in African Americans is indeed a distinct clinical entity.     

Youth-onset type 2 diabetes mellitus—a distinct entity?

International Journal of Diabetes in Developing Countries -