Assessment of portal hypertension severity using machine learning models in patients with compensated cirrhosis

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Duplex-Doppler assessment of cirrhosis in patients with chronic compensated liver disease

Portal venous flow velocity (PFV) was measured with duplex-Doppler equipment in 50 normal subjects and in 117 patients with suspected chronic liver disease who showed no evidence of decompensation such as ascites, hepatic encephalopathy, jaundice or oesophageal bleeding. All the patients underwent percutaneous liver biopsy which demonstrated non-cirrhotic liver disease in 58 cases (CH-patients: steatosis 8, persistent chronic hepatitis 8, active chronic hepatitis 42) and liver cirrhosis in the other 59 cases (LC-patients). The normal subjects and the CH-patients had similar values of max-PFV and mean-PFV (max-PFV 26.7±3.2 and 25.7±3.4 cm/s respectively; mean-PFV 22.9±2.8 and 22.4±3.8 cm/s respectively). The LC-patients’ values (max-PFV 19.3±3.5; mean-PFV 16.9±2.9) were significantly lower than those of the normal subjects (P<0.001) and of the CH-patients (P<0.001). Considering the normal max-PFV to be in the range 20–33.1 cm/s (mean±2 s.d. of the normal subjects, 95% confidence limits), max-PFV was reduced in 0/50 normal subjects, 1/58 CH-patients and 39/59 LC-patients (66.1% sensitivity; 98.2% specificity). In conclusion, the duplex-Doppler measurement of PFV is of great interest in the diagnostic study of patients with suspected chronic compensated liver disease and in the early diagnosis of cirrhosis. A low max-PFV is a reliable pointer to liver cirrhosis, whereas a normal max-PFV indicates a non-cirrhotic liver disease but is less probative. Each centre should standardize normal PFV values in order to establish their own threshold value for diagnosing liver cirrhosis.     

Biliary lipid composition in patients with non-cirrhotic portal fibrosis--a comparison with compensated cirrhosis of the liver

Patients with non-cirrhotic portal fibrosis (NCPF) are known to have mild hepatic functional abnormalities. To study the biliary lipid composition in these patients, duodenal bile was collected from 18 patients with NCPF, 15 patients with non-alcoholic compensated cirrhosis of the liver and 18 matched, non-obese, healthy control subjects. There were no significant differences in the mean (+/- SD) concentrations of cholesterol, phospholipids and bile acids in patients with NCPF and healthy controls. On the other hand, patients with cirrhosis had significantly lower concentrations of all the three biliary lipids as compared with the NCPF patients and controls (p less than 0.05). The cholesterol solubilizing capacity of the bile was the same in NCPF patients, cirrhotics and controls. It is concluded that the relative proportions of the three biliary lipids remain unchanged in patients with NCPF despite mild hepatic derangement.     

Mineralocorticoid escape in patients with compensated cirrhosis and portal hypertension.

Failure to escape from mineralocorticoids in compensated cirrhosis is considered a major argument supporting the overflow theory of ascites. To assess the frequency and mechanism of mineralocorticoid escape in cirrhosis, 9-alpha-fluorohydrocortisone (0.6 mg/day) was administered to 19 patients with compensated cirrhosis, portal hypertension, and no history of ascites who were able to maintain sodium balance on a 250 mmol Na+ diet. Fifteen patients (78.9%) escaped from mineralocorticoids, while 4 patients (21.1%) did not escape and developed ascites. Patients who did not escape had significantly higher cardiac index (4.97 +/- 0.42 vs 3.46 +/- 0.21 L.min-1.m-2) and lower peripheral vascular resistance (485.9 +/- 37.5 vs. 665.8 +/- 32.9 dyne.s.cm-5/m2) than those who escaped. Hepatic venous pressure gradient was not significantly different. The escape phenomenon was associated with a significant increase in mean arterial pressure, creatinine clearance, and atrial natriuretic factor and suppression of plasma renin activity. All of these parameters showed minimal or no changes in patients who did not escape. These results indicate that failure to escape from mineralocorticoids is uncommon in patients with compensated cirrhosis, is related to an inadequate expansion of effective plasma volume due to the accumulation of ascites, and occurs in patients with marked peripheral arteriolar vasodilation.     

Noninvasive prediction of clinically significant portal hypertension and esophageal varices in patients with compensated liver cirrhosis

OBJECTIVES: We aimed to develop a model based on noninvasive variables for the prediction of clinically significant portal hypertension (CSPH) and of esophageal varices (EV) in patients with compensated liver disease.
METHODS: Sixty patients with compensated liver cirrhosis diagnosed by histology were included in the training set. All patients had physical examination, laboratory tests, abdominal color-Doppler ultrasound, upper digestive tract endoscopy, and measurement of hepatic venous pressure gradient. Predictive models for the presence of CSPH and of EV were calculated. The models were validated in an independent series of 74 patients with compensated liver disease.
RESULTS: Clinical and laboratory variables were selected in the final models, while ultrasonography did not add statistical power for the prediction of CSPH and EV. The model for prediction of CSPH included albumin, INR, and ALT. The best cutoff had 93% sensitivity and 61% specificity in the training set, and correctly classified 77% of patients in the validation set. Spider angiomas, ALT, and albumin predicted EV. The best cutoff of the model in the training set had a sensitivity of 93% and a specificity of 37% and correctly classified 72% of cases in the validation set.
CONCLUSIONS: Noninvasive prediction of EV in well-compensated cirrhotic patients is not accurate. However, a model obtained by combining simple laboratory variables has a high sensitivity to predict CSPH in this population and may be useful to select the subset of patients requiring screening endoscopy. By this method, endoscopic screening could be obviated in about 40% of patients.     

Enhanced renal ammonia excretion following volume expansion in patients with well compensated cirrhosis of the liver

BACKGROUND AND AIMS: In patients with cirrhosis, hepatic encephalopathy is often precipitated by dehydration. This study tests the hypothesis that volume expansion in cirrhotic patients increases renal ammonia excretion. PATIENTS AND METHODS: Sixteen well compensated cirrhotic patients (mean Pugh score 6.7 (SEM 0.4)) were studied after an overnight fast. One litre of 0.9% saline was administered to patients intravenously over one hour. Plasma and urinary ammonia and sodium, renal plasma flow (RPF), glomerular filtration rate (GFR), plasma renin activity (PRA), and angiotensin II (ANG II) were measured before, during, and two hours after saline infusion. RESULTS: Saline infusion resulted in a significant reduction in plasma ammonia (93 (SEM 7) to 56 (4) micromol/l; p<0.05) and RPF and GFR increased (p<0.05). Urinary ammonia excretion increased (p<0.05) significantly. There was a significant reduction in ANG II and PRA (p<0.05 for each) and the change in ammonia excretion correlated directly with the change in urinary sodium excretion (p<0.007), ANG II (p<0.002), and PRA (p<0.01). The mean increase in urinary ammonia excretion during the observation period was 1.08 mmol. Assuming a volume of distribution of 45 litres, the corresponding change in whole body ammonia during the same period was 1.67 mmol. CONCLUSION: The results of this study suggest that volume expansion reduces plasma ammonia concentration by increasing ammonia excretion and reducing ammoniagenesis.     

The free portal pressure in awake patients with and without cirrhosis of the liver

ABSTRACT— The free portal pressure was measured by percutaneous transhepatic catheterization of the portal vein in 106 patients with cirrhosis of the liver and in 19 patients without liver disease and with normal portography. Patients with cirrhosis had a median portal pressure of 38 cmH₂O and patients without liver disease had a median portal pressure of 16 cmH₂O. Among the cirrhotic patients the free portal pressure showed no relationship to etiology of cirrhosis, ascites, variceal bleedings or extrahepatic shunting. The median portal pressure was significantly higher in patients with (40 cmH₂O) than without (30 cmH₂O) gastroesophageal varices (p<0.01). The pressure was not related to the size of the varices.     

Cardiac dysfunction in cirrhosis is not associated with the severity of liver disease

BackgroundCirrhotic cardiomiopathy is described as the presence of cardiac dysfunction in cirrhotic patients. The aim of the study was to investigate factors associated with cardiac dysfunction in cirrhotic patients.Patients and methodsSeventy-four cirrhotic patients and twenty-six controls performed a conventional echocardiography and Tissue Doppler Imaging (TDI) for systolic and diastolic function. Results were analyzed by using the Guidelines of American Society of Echocardiography.ResultsIn patients with cirrhosis, left ventricular end-diastolic diameter was increased (p < 0.001) , peak systolic velocities were decreased (11.3 ± 2.7 vs 13.9 ± 1.4 cm/s; p < 0.001) and left atrial volumes were increased (32.7 ± 8.3 vs 24 ± 8.5 ml, p < 0.001) as well as cardiac mass (90.6 ± 23 vs 70.5 ± 22 g/m², p < 0.001). Forty-seven cirrhotic patients (64%) showed diastolic dysfunction at rest: grade I in 37 and grade II in 10 patients. Systolic and/or diastolic dysfunction were not influenced by a more severe liver impairment. Diastolic dysfunction was more prevalent in patients with ascites vs those without (77% vs 56%; p = 0.04).ConclusionA mild diastolic dysfunction at rest is frequent in cirrhotic patients but cardiac load conditions are confounding factors in this diagnosis. We did not identify an association between severity of liver disease and cardiac dysfunction.     

Variceal pressure is a strong predictor of variceal haemorrhage in patients with cirrhosis as well as in patients with non-cirrhotic portal hypertension

BACKGROUND: Variceal pressure is a strong predictor for a first variceal bleed in patients with cirrhosis. AIMS: To evaluate whether variceal pressure is also a determinant of the risk of a first variceal bleed in patients with non-cirrhotic portal hypertension. METHODS: Variceal pressure was measured non-invasively in 25 patients with non-cirrhotic portal hypertension and large varices while receiving a stable therapeutic regimen. Factors predictive of bleeding were compared with those observed in 87 cirrhotics. RESULTS: The one year incidence of variceal bleeding was 32% (n=28) for the cirrhotic and 20% (n=5) for the non-cirrhotic patients. There was no difference in factors predicting the risk of bleeding between the groups, except for variceal pressure. For the same level of variceal pressure, the risk of variceal bleeding was lower in patients with non-cirrhotic portal hypertension. Multiple logistic regression analysis revealed the following variables as having a significant predictive power: variceal pressure (p=0.0001), red spots (p=0.004), and the time interval between the first observation of the varices and the moment of variceal pressure measurement (p=0. 0046). For the non-cirrhotics the risk of bleeding increased with higher Child-Pugh score (p=0.0024); this was not the case for the cirrhotic patients (p=0.9521). CONCLUSION: Variceal pressure is a major predictor of variceal bleeding in patients with cirrhosis as well as in patients with non-cirrhotic portal hypertension. The risk of bleeding in non-cirrhotics is less than in cirrhotics for the same level of variceal pressure. In patients with non-cirrhotic portal hypertension the risk of variceal bleeding increases more with advancing disease.     

Effect of cimetidine on portal pressure and systemic hemodynamics in patients with and without liver cirrhosis

Portal pressure and systemic hemodynamics were evaluated for 30 minutes after intravenous injection of 400 mg of cimetidine in patients with and without liver cirrhosis when they were operated upon for varying surgical diseases. A transient fall of arterial pressure was seen in both groups of patients, but the change was statistically significant only in those with cirrhosis. Cimetidine did not substantially alter pulse rate, CVP, and portal pressure in both groups. The present results seem to indicate that rapid administration of cimetidine does not induce a fall of portal venous pressure in both cirrhotic and non-cirrhotic patients.     

Impact of liver disease severity and etiology on the occurrence of diabetes mellitus in patients with liver cirrhosis

The association between liver cirrhosis (LC) and diabetes mellitus (DM) is well known. However, the impact of the severity or etiology of LC on the occurrence of DM is relatively unknown. We aimed to determine the prevalence and clinical correlates of DM in a large cohort of patients with cirrhosis. A total of 1,068 patients with LC were included in this cross sectional study (CIRCE study). The diagnosis of cirrhosis irrespective of its etiology was based on histological confirmation by liver biopsy or, in the absence of biopsy, on typical clinical, morphological and biological data. Data related to the cirrhosis etiology: alcohol, viral markers of hepatitis B, C, iron load parameters and autoimmune markers were collected for each patient. Venous blood samples were taken in the morning after 12-h overnight fasting. There were 383 patients with cirrhosis associated with hepatocellular carcinoma (HCC). DM was found in 412 (39.7 %) patients. Patients with DM were older and more likely to be overweight and male, with a family history of DM and a diagnosis of HCC. DM was not associated with a history of stroke or myocardial infarction. Cirrhosis secondary to hepatitis infection was less strongly associated with DM than with NASH or alcoholic cirrhosis. The severity of LC was not associated with DM. In multivariate analysis, the factors associated with DM were age, BMI, a family history of DM, and statin use. There was a significant interaction between HCC and cirrhosis etiology for the risk of DM. Cirrhosis secondary to hepatitis was associated with a lesser presence of DM only in patients with HCC (interaction p = 0.0015). LC was strongly associated with DM, with around 40 % of diabetic patients. In the group of patients with LC without HCC, diabetes was not associated with the etiology of cirrhosis.     

Biliary lipid composition in patients with non-cirrhotic portal fibrosis – a comparison with compensated cirrhosis of the liver

ABSTRACT— Patients with non-cirrhotic portal fibrosis (NCPF) are known to have mild hepatic functional abnormalities. To study the biliary lipid composition in these patients, duodenal bile was collected from 18 patients with NCPF, 15 patients with non-alcoholic compensated cirrhosis of the liver and 18 matched, non-obese, healthy control subjects. There were no significant differences in the mean (± SD) concentrations of cholesterol, phospholipids and bile acids in patients with NCPF and healthy controls. On the other hand, patients with cirrhosis had significantly lower concentrations of all the three biliary lipids as compared with the NCPF patients and controls (p<0.05). The cholesterol solubilizing capacity of the bile was the same in NCPF patients, cirrhotics and controls. It is concluded that the relative proportions of the three biliary lipids remain unchanged in patients with NCPF despite mild hepatic derangement.     

Systemic and pulmonary hemodynamics in patients with non-cirrhotic portal fibrosis (NCPF) is similar to compensated cirrhosis

Background Non-cirrhotic portal fibrosis (NCPF) is an important cause of portal hypertension (PHT) and variceal bleeding, especially in the developing countries. While the hepatic parenchyma and liver functions are normal, the patho-anatomic defect in these patients is pre- and peri-sinusoidal in nature. Aim To study the systemic and pulmonary hemodynamic alterations in patients with NCPF and compare them with compensated cirrhotic patients. Patients and Methods Patients with NCPF (n = 20, mean age 29.3 ± 9.8 year) and matched Child’s A cirrhotic patients (n = 17, age 34.1 ± 9.8 year) who had bled in the past, underwent hemodynamic measurements using a balloon tipped catheter. Results In NCPF patients, the hepatic venous pressure gradient (HVPG) was significantly lower than in the cirrhotic patients (4.9 ± 1.5 mmHg vs. 15.7 ± 4.5 mmHg; P < 0.01). NCPF patients had hyperdynamic circulation and peripheral vasodilatation comparable to cirrhotic patients; cardiac output (8.0 ± 1.2 l/min vs. 8.4 ± 1.9 l/min; P = 0.4), cardiac index (5.4 ± 0.8 l/min/m² vs. 5.5 ± 1.9 l/min/m²; P = 0.86), mean arterial pressure (88.2 ± 14.1 mmHg vs. 89.9 ± 17.3 mmHg; P = 0.73), systemic vascular resistance (852.8 ± 204.3 dynes · s/cm⁵ vs. 854.1 ± 189.9 dynes · s/cm⁵; P = 0.98) and pulmonary vascular resistance (41.6 ± 18.1 dynes · s/cm⁵ vs. 41.3 ± 17.9 dynes · s/cm⁵; P = 0.95) were comparable in the two groups. Conclusions NCPF associated portal hypertension leads to a hyperdynamic state with high cardiac index and low systemic and pulmonary vascular resistance comparable to compensated cirrhosis. These novel observations suggest a primary role of portal hypertension in the development of hyperdynamic state.     

Albumin-binding function is reduced in patients with decompensated cirrhosis and correlates inversely with severity of liver disease assessed by model for end-stage liver disease

BACKGROUND: Human serum albumin has multiple functions, the most important being maintaining colloid osmotic pressure, ligand binding and transport. In liver failure, an impaired binding of endogenous substances and drugs can be observed. The aim of this study was to investigate the relationship between the severity of liver disease and an impaired albumin binding. METHODS: In 44 patients with decompensated liver cirrhosis, Child-Turcotte-Pugh and model for end-stage liver disease scores were assessed and the site II-specific albumin-binding function (albumin-binding capacity) was characterized. Briefly, the unbound amount of diazepam site ligand Dansylsarcosine in a sample was determined and compared with the unbound amount in a reference albumin solution (=100%). RESULTS: Thirty-two out of 44 of the patients presented with Child-Turcotte-Pugh class C, the median Child-Turcotte-Pugh score was 10 [6-13 (min-max)], median model for end-stage liver disease score was 21 (8-40) and the median albumin-binding capacity was 63 (24-91)% compared with healthy controls 98 (95-106)% (P<0.001). Albumin-binding capacity was found to be strongly correlated to model for end-stage liver disease (r=0.783; P<0.001). CONCLUSIONS: An impaired albumin-binding function of a site II-specific marker in decompensated liver cirrhosis was found to be correlated to the severity of the liver disease.     

Health-related quality of life in patients with compensated and decompensated liver cirrhosis

BackgroundCompensated (Child-Pugh [CP] A) and decompensated (CP B/C) liver cirrhosis significantly differs in terms of impairment of health-related quality of life (HRQoL). However, sufficient data on potentially treatable factors associated with HRQoL in both stages of the disease are still lacking. Consequently, aims of this study were to determine differences in HRQoL between patients with compensated and decompensated liver cirrhosis and to identify potentially treatable factors associated with HRQoL.Methods218 patients with liver cirrhosis were enrolled into this study. Chronic Liver Disease Questionnaire (CLDQ) was used to assess HRQoL. Covert hepatic encephalopathy (CHE) was diagnosed according to a combination of Psychometric Hepatic Encephalopathy Score and Critical Flicker Frequency. Frailty was assessed by Clinical Frailty Scale (CFS).ResultsHRQoL differed between patients with CP A (n = 133) and CP B/C (n = 85) liver cirrhosis (CLDQ total score: 5.6 vs. 4.8, p < 0.001). Multivariate analysis identified a history of falls in the recent year, presence of CHE, female gender, active smoking, higher CFS, and higher serum levels of CRP as independent predictors of impaired HRQoL (all p < 0.05) in patients with CP A liver cirrhosis. In patients with CP B/C liver cirrhosis, female gender, a history of overt hepatic encephalopathy, and lower hemoglobin were independently associated with impaired HRQoL (all p < 0.05).ConclusionsPredictors of impaired HRQoL differ in patients with CP A or CP B/C liver cirrhosis. Focusing on treatable factors in routine clinical practice may improve HRQoL in all stages of liver cirrhosis.     

Adipokines levels are associated with the severity of liver disease in patients with alcoholic cirrhosis

AIM:To investigate the adipokine levels of leptin,adiponectin,resistin,visfatin,retinol-binding protein 4(RBP4),apelin in alcoholic liver cirrhosis(ALC).METHODS:Forty non-diabetic ALC patients[median age:59 years,males:35(87.5%),Child-Pugh(CP)score:median 7(5-12),CP A/B/C:18/10/12,Model for End-stage Liver Disease(MELD):median 10(6-25),follow-up:median 32.5 mo(10-43)]were prospectively included.The serum adipokine levels were estimated in duplicate by ELISA.Somatometric characteristics were assessed with tetrapolar bioelectrical impedance analysis.Pearson’s rank correlation coefficient was used to assess possible associations with adipokine levels.Univariate and multivariate Cox regression analysis was used to determine independent predictors for overallsurvival.RESULTS:Body mass index:median 25.9(range:20.1-39.3),fat:23.4%(7.6-42.1),fat mass:17.8(5.49-45.4),free fat mass:56.1(39.6-74.4),total body water(TBW):40.6(29.8-58.8).Leptin and visfatin levels were positively associated with fat mass(P0.001/P=0.027,respectively)and RBP4 with TBW(P=0.025).Median adiponectin levels were significantly higher in CPC compared to CPA(CPA:7.99±14.07,CPB:7.66±3.48,CPC:25.73±26.8,P=0.04),whereas median RBP4 and apelin levels decreased across the spectrum of disease severity(P=0.006/P=0.034,respectively).Following adjustment for fat mass,visfatin and adiponectin levels were significantly increased from CPA to CPC(both P0.001),whereas an inverse correlation was observed for both RBP4 and apelin(both P0.001).In the multivariate Cox regression analysis,only MELD had an independent association with overall survival(HR=1.53,95%CI:1.05-2.32;P=0.029).CONCLUSION:Adipokines are associated with deteriorating liver function in a complex manner in patients with alcoholic liver cirrhosis.     

Relation between severity of liver disease and renal oxygen consumption in patients with cirrhosis

BACKGROUND: Worsening cirrhosis may lead to increased renal O2 metabolism caused by activation of neurohumoral antinatriuretic substances. AIMS: To evaluate the relation between the severity of liver disease, sodium excretion, and neurohumoral antinatriuretic substances on the one hand and renal O2 metabolism on the other in patients with cirrhosis. METHODS: Renal O2 consumption and haemodynamics as well as plasma concentrations of noradrenaline, renin, and aldosterone were measured. Investigations were performed in 14 patients with Pugh's grade A, 43 with grade B, and 29 with grade C liver disease. RESULTS: Renal O2 consumption significantly increased with the severity of cirrhosis (grade A, 8.9 (1.6); grade B, 15.5 (1.3); grade C, 18.0 (1.5) ml/min/m2). Plasma concentrations of noradrenaline, renin, and aldosterone significantly increased while mean arterial presssure and systemic vascular resistance significantly decreased with the severity of the disease. A significant inverse correlation was found between renal O2 consumption and sodium excretion. A significant direct correlation was found between plasma levels of noradrenaline and aldosterone on the one hand and renal O2 consumption on the other. Renal blood flow and the glomerular filtration rate did not differ significantly between patients with grade C and grade A or B disease. CONCLUSIONS: This study shows for the first time that, in patients with cirrhosis, worsening of the disease is associated with an increase in renal O2 consumption. The results suggest that increased renal O2 consumption is due to renal tubular sodium retention caused by increased levels of neurohumoral antinatriuretic substances. This neurohumoral activation is related to cirrhosis induced vasodilation.