Gabriele Forlani

Obesity-Associated Liver Disease

CONTEXT In the last few years, several data have accumulated suggesting that obesity may be associated with liver disease and disease progression. Accordingly, the worldwide epidemic of obesity is likely to become a relevant source of morbidity and mortality in the general population. EVIDENCE ACQUISITION We reviewed the literature on two main issues: 1) the evidence that obesity carries out an increased risk of liver disease, both in the general population and in selected cohorts; and 2) the evidence that obesity is a risk factor for nonalcoholic fatty liver disease and its progression in a series observed in liver units. EVIDENCE SYNTHESIS The presence of obesity increases the risk of elevated liver enzymes by a factor of two to three, whereas the risk of steatosis at ultrasonography is increased by a factor of 3 in the presence of overweight and peaks at a factor of approximately 15 in the presence of obesity. Both cirrhosis (cryptogenic cirrhosis) and hepatocellular carcinoma are also associated with obesity in the general population. In patients with nonalcoholic fatty liver disease observed in liver units, obesity and weight gain are systematically associated with advanced fibrosis and fibrosis progression. CONCLUSION Liver disease of metabolic origin, associated with obesity, is now recognized as the most prevalent liver disease in Western countries. Strategies are needed to approach obesity-associated liver disease by behavior programs, motivating people to adopt a healthier lifestyle. Such programs should be coupled with public policies at a societal level to obtain the maximum effects in lifestyle changes.

Lipid Abnormalities in Insulin-dependent Diabetic Patients with Albuminuria

The relationship between serum lipid, lipoprotein, and apolipoprotein levels and abnormalities of renal function has been investigated in 112 insulin-dependent (type I) diabetic patients. They were subdivided into three matched groups according to the amount of albuminuria: group A (albuminuria < 20 μg/min), group B (albuminuria between 20 and 150 μg/min; Albustix negative), and group C (albuminuria > 150 μg/min; Albustix positive). Twenty-one nondiabetic subjects with albuminuria above 150 μg/min but without nephrotic syndrome and/or renal failure and 77 healthy subjects were also studied. Mean total and LDL cholesterol, triglycerides, and apo B were higher, while HDL cholesterol and HDL/LDLcholesterol ratio were lower in group C than in groups A and B; the apo A/apo B ratio was lower in group C than in group A. Differences in apo B and in apo A/apo B ratio were found between groups A and B. No correlation between lipid parameters and amount of albuminuria was observed. Significant differences in lipid concentrations were also found in diabetic patients when compared with nondiabetic subjects with albuminuria and with healthy subjects. The present study confirmed previous reports of lipid disorders in insulin-dependent (type I) diabetes; however, the most important observation was the finding of albuminuria-related differences in lipid parameters in diabetic patients without renal failure. We think that the greater lipid abnormalities observed in diabetic patients with larger amounts of albuminuria might be the consequence both of impairment of glomerular permeability and of the diabetic state.

Cardiovascular disease in cirrhosis--a point-prevalence study in relation to glucose tolerance.

OBJECTIVE:Impaired glucose tolerance or diabetes are frequently observed in cirrhosis. Overt diabetes was reported to affect long term survival of cirrhotic patients by increasing the risk of hepatocellular failure, without increasing the risk of diabetes-associated cardiovascular events.METHODS:We evaluated the prevalence of cardiovascular disease in 122 patients with cirrhosis, subdivided according to their glucose tolerance. The following parameters were considered: arterial pressure, peripheral vascular disease (ankle to brachial pressure ratio), ischemic heart disease, microalbuminuria, retinopathy. The prevalence of abnormal findings was compared with that observed in 60 randomly selected patients with non–insulin-dependent diabetes and in 40 controls.RESULTS:Noninsulin-dependent diabetic patients and patients with cirrhosis and diabetes were comparable for age, metabolic control, and smoking habits; the duration of diabetes was 5 yr longer for noninsulin-dependent diabetes. In cirrhosis, the prevalence of micro- and peripheral macroangiopathy, as well as coronary heart disease, was not different in relation to glucose tolerance, it was comparable to that of controls, and significantly lower than that observed in noninsulin-dependent diabetes.CONCLUSIONS:Cirrhotic patients, even in the presence of overt diabetes, are at low risk of cardiovascular disease. The low prevalence may be related to shorter duration of diabetic disease, also in relation to reduced life expectancy, as well as to liver disease-induced abnormalities protecting the cardiovascular system from atherosclerosis.

Insulin and glucagon levels in liver cirrhosis

Alterations in insulin and glucagon levels migh account for the plasma amino acid imbalance of cirrhotics. In order to verify this hypothesis we evaluated basal insulin, glucagon, branched-chain amino acids, aromatic amino acids, and free tryptophan in 13 controls and 37 cirrhotics divided on the basis of their mental state; in 4 patients the hormonal and amino acid patterns were sequentially studied during various stages of encephalopathy. Glucagon is high in cirrhotics and progressively increases with the worsening of the mental state. Free tryptophan and aromatic amino acids show a similar behavior and significantly correlate with glucagon levels (r=0.67 and r=0.81, respectively). On the other hand insulin levels, which are high in cirrhotics without encephalopathy, fall in the presence of deep coma. Insulin did not correlated with any of the plasma amino acids considered. Our data suggest that the catabolic state associated with increased glucagon levels may account for some of the alterations in the plasma amino acid profiles of cirrhotics. Portal-systemic shunting does not seem to be the common cause of both hyperglucagonemia and hyperaminoacidemia. Decreased branched-chain amino acid levels may be related to factors different from those involved in the alterations of carbohydrate homeostasis.

Is liver disease a threat to patients with metabolic disorders

The association of metabolic disorders with liver disease is receiving increasing attention in the gastroenterological community. Cohort studies have shown that advanced liver disease may stem from metabolic disorders, via fatty liver, non‐alcoholic steatohepatitis, cryptogenic cirrhosis, and eventually hepatocellular carcinoma. In both obesity and diabetes, deaths from cirrhosis are higher than expected, mainly in subjects with no or moderate alcohol consumption, but high rates of fatty liver disease have been associated with all features of the metabolic syndrome. Also the risk of hepatocellular carcinoma is higher than normal, being dependent on body mass index (BMI) in obesity, and independent of age, BMI, gender and race in diabetes. Finally, metabolic liver disease may interact with hepatitis C virus infection, increasing the risk of steatosis and liver disease progression, as well as reducing the chances of an effective antiviral treatment. There is evidence that treatments aimed at reducing insulin resistance are also effective in improving liver histology. Although cardiovascular disease remains the major cause of increased morbidity and excess mortality in metabolic disorders, the risk of progressive liver disease should no longer be underestimated, being a threat to millions of people at risk in the present epidemics of obesity and diabetes, and therapeutic strategies need to be tested.

Double-heterozygous mutations involving both HNF1A (MODY3) and HNF4A (MODY1) genes: a case report

OBJECTIVE We describe a maturity-onset diabetes of the young (MODY) case with mutations involving both HNF4A and HNF1A genes. RESEARCH DESIGN AND METHODS A male patient was diagnosed with diabetes at age 17; the metabolic control rapidly worsened to insulin requirement. At that time no relatives were known to be affected by diabetes, which was diagnosed years later in both the parents (father at age 50 years, mother at age 54 years) and the sister (at age 32 years, during pregnancy). RESULTS The genetic screening showed a double heterozygosity for the mutation p.E508K in the HNF1A/MODY3 gene and the novel variant p.R80Q in the HNF4A/MODY1 gene. The genetic testing of the family showed that the father carried the MODY3 mutation while the mother, the sister, and her two children carried the MODY1 mutation. CONCLUSIONS MODY1 and MODY3 mutations may interact by chance to give a more severe form of diabetes (younger age at presentation and early need of insulin therapy to control hyperglycemia).

Homocysteine and psychological traits: a study in obesity

OBJECTIVE Total serum homocysteine is a risk factor for cardiovascular disease in the general population. Further, homocysteine might be the link between psychological traits (namely anger and hostility) and cardiovascular disease, mediated by stressful events and sympathetic nervous tone. METHODS We measured total plasma homocysteine levels and psychological traits in 205 obese individuals entering a weight-reduction program (162 females; age range, 17-64 years; body mass index, 37.7 +/- 6.2 kg/m(2), mean +/- standard deviation). Psychometric assessment was performed with three self-administered questionnaires (Symptom Checklist 90, composed of nine subscales including Hostility/Anger and Depression scales; Beck Depression Inventory; and Binge Eating Scale). RESULTS Homocysteine levels were moderately increased in obese individuals when compared with the normal population and higher in males (median, 12.9 micromol/L; range, 6.9-26.3) than in females (9.8; 4.6-24.6; P < 0.0002), but not different in relation to the severity of obesity. Serum folate and vitamin B12 were normal. Psychometric testing showed pathologic data in up to 50% of patients and the Anger/Hostility scale was positive in 24%, mainly female, subjects. There were no differences in psychological traits in relation to the severity of obesity. Homocysteine did not correlate with Symptom Checklist 90 values or other values of psychometric testing. CONCLUSIONS In obese persons, psychological traits are not major determinants of total homocysteine. A different response to stressful events, not simply mediated by sympathetic nervous tone, might be present in obesity.

Hyperglycemic Effect of Sucrose Ingestion in IDDM Patients Controlled by Artificial Pancreas

The hyperglycemic effect of 28 g sucrose, taken during a mixed meal, was studied in six insulin-dependent diabetes mellitus (IDDM) patients controlled by artificial pancreas. On 2 consecutive days the patients were given, in random order, two Italian meals containing macaroni, bread, meat, vegetables, fruit, olive oil, and an eggnog made with sucrose (meal A) or saccharin (meal B). The two meals were isocaloric and contained equal amounts of carbohydrates. The feedback control on blood glucose continued for 180 min after the meals. Plasma glucose levels and insulin infusion rates delivered by the artificial pancreas after the two test meals did not show any significant differences regarding basal and peak values, peak times, and areas under the curves. A modest amount of sucrose, taken during a mixed meal, does not produce a hyperglycemic effect higher than an equal amount of complex carbohydrates in IDDM patients controlled by artificial pancreas. The same may be expected in well-controlled IDDM patients in conventional therapy because a correlation exists between insulin requirement for conventional therapy and insulin delivered during glucose-controlled insulin infusion.

The management of severe hypoglycemia by the emergency system: The HYPOTHESIS study

BACKGROUND AND AIMS Severe hypoglycemia is not rare in diabetes and markedly impacts on health resource use. We aimed to describe the characteristics of patients attending emergency departments (EDs) following a severe episode of hypoglycemia, the factors associated with the management of events and the final outcome. METHODS AND RESULTS We carried out a retrospective analysis of cases attending 46 Italian EDs for hypoglycemia from January 2011 to June 2012. A total of 3753 records were retrieved from the databases of the participating centers, part of a network repeatedly involved in collaborative studies; 3516 episodes occurred in subjects with diabetes (median age, 76 years; range, 1-102). Comorbidities were recorded in 2320 (65.9%) diabetes cases; association with trauma or road accidents in 287 (8.2%) and 47 (1.3%), respectively. Patients were treated with insulin (49.8%), oral agents (31.4%), or combination treatment (15.1%). The event required assistance by the out-of-hospital Emergency services in 1821 cases (51.8%). Following the ED visit, admission to hospital departments was deemed necessary in 1161 cases (33.1%). Diabetes treatment (oral agents: OR, 1.63; 95% confidence interval (CI), 1.37-1.94), increasing age (OR, 1.39; 95% CI, 1.31-1.48) and the number of comorbidities (OR, 1.51; 95% CI, 1.38-1.66) were the main drivers of admission. The in-hospital death rate was 10%, associated with the number of comorbidities (OR, 1.28; 95%CI, 1.01-1.63). CONCLUSION Severe hypoglycemia requiring referral to EDs is associated with a significant work-up of the Emergency services and a remarkable in-hospital death rate in frail individuals with diabetes.

Long-term effects of eating sucrose on metabolic control of type 1 (insulin-dependent) diabetic outpatients

SummaryThe aim of the study was to investigate the effects of regularly eating a moderate amount of sucrose (30 g/day) in 12 type 1 (insulin-dependent, IDDM) diabetic outpatients in fair blood glucose and lipid control. Two diets, each lasting two month, were compared in a randomized cross-over study. The former was a high-carbohydrate high-fiber diet for diabetic patients with Italian alimentary habits, the latter had the same composition except that 30 g of sucrose replaced 30 g of complex carbohydrates with high glycemic index (bread). The two diets contained equal amounts of carbohydrates, proteins and lipids; the only difference being the contribution of oligosaccharides to total carbodhydrates (22%vs 34%) and cholesterol amount. During the control diet, glycosylated hemoglobin was substantially unchanged in both control and sucrose diet periods (control diet: 6.91±0.29 (SE)vs 6.80±0.25%; sucrose diet: 6.75±0.31vs 6.91±0.36%). This was true also for fructosamine (control diet: 3.92±0.21vs 3.76±0.18%; sucrose diet: 3.50±0.14vs 3.64±0.20 mmol/l). Circulating blood lipid levels, body weight and daily insulin dose did not show any significant variations during the study. Moderate amounts of sucrose may be allowed to IDDM patients with Italian alimentary habits without worsening diabetic control.