The Danish comorbidity in liver transplant recipients study (DACOLT): a non-interventional prospective observational cohort study.

BACKGROUND: Liver transplantation is the only curative treatment for patients with end-stage liver disease. Short-term survival has improved due to improved surgical techniques and greater efficacy of immunosuppressive drugs. However, long-term survival has not improved to the same extent as the short-term survival, and the 10-year survival after liver transplantation is 60%. In addition to liver- and transplant-related causes, comorbidities such as cardiovascular, pulmonary, renal, and metabolic diseases have emerged as leading causes of morbidity and mortality in liver transplant recipients. The objective of this study is to assess the burden of comorbidities and identify both liver- and transplant-related risk factors as well as traditional risk factors that contribute to the pathogenesis of comorbidity in liver transplant recipients. METHODS/DESIGN: The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study is an observational, longitudinal study. We aim to include all adult liver transplant recipients in Denmark (n = approx. 600). Participants will be matched by sex and age to controls from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). Physical and biological measures including blood pressure, ankle-brachial index, spirometry, exhaled nitric oxide, electrocardiogram, transthoracic echocardiography, computed tomography (CT) angiography of the heart, unenhanced CT of chest and abdomen and blood samples will be collected using uniform protocols in participants in DACOLT, CGPS, and CCHS. Blood samples will be collected and stored in a research biobank. Follow-up examinations at regular intervals up to 10 years of follow-up are planned. DISCUSSION: There is no international consensus standard for optimal clinical care or monitoring of liver transplant recipients. This study will determine prevalence, incidence and risk factors for comorbidity in liver transplant recipients and may be used to provide evidence for guidelines on management, treatment and screening and thereby contribute to improvement of the long-term survival. Trial registration ClinicalTrials.gov: NCT04777032; date of registration: March 02, 2021.

[Primary membranous nephropathy presenting as relapsing ascites].

Ascites is common in patients with liver cirrhosis. It may present as a clinical manifestation in nephrotic syndrome in adults, typically with heart- or liver disease together with other oedema. We describe a 64-year-old male patient - with no liver or heart disease - with relapsing ascites and no other oedema, who was surprisingly diagnosed with primary membranous nephropathy (MN), and the autoantibody anti-PLA2R was positive. Through immunotherapy the ascites disappeared. Anti-PLA2R and anti-TSHD7A can be used in the diagnosis (primary/secondary MN) and may play a role in the treatment and prognosis.

Cerebral metabolic disturbances in the brain during acute liver failure: from hyperammonemia to energy failure and proteolysis.

Several observations suggest that patients with fulminant hepatic failure may suffer from disturbances in cerebral metabolism that can be related to elevated levels of arterial ammonia. One effect of ammonia is the inhibition of the rate limiting TCA cycle enzyme alpha-ketoglutarate dehydrogenase (alphaKGDH) and possibly also pyruvate dehydrogenase, but this has been regarded to be of no quantitative importance. However, recent studies justify a revision of this point of view. Based on published data, the following sequence of events is proposed. Inhibition of alphaKGDH both enhances the detoxification of ammonia by formation of glutamine from alpha-ketoglutarate and reduces the rate of NADH and oxidative ATP production in astrocytic mitochondria. In the astrocytic cytosol this will lead to formation of lactate even in the presence of sufficient oxygen supply. Since the aspartate-malate shuttle is compromised, there is a risk of depletion of mitochondrial NADH and ATP unless compensatory mechanisms are recruited. One likely compensatory mechanism is the use of amino acids for energy production. Branched chain amino acids, like isoleucine and valine can supply carbon skeletons that bypass the alphaKGDH inhibition and maintain TCA cycle activity. Large-scale consumption of certain amino acids can only be maintained by cerebral proteolysis, as has been observed in these patients. This hypothesis provides a link between hyperammonemia, ammonia detoxification by glutamine production, cerebral lactate production, and cerebral catabolic proteolysis in patients with FHF.

Kidneys extract BNP and NT-proBNP in healthy young men.

Renal metabolism of the cardiac marker NH2-terminal-pro-brain natriuretic peptide (NT-proBNP) has been suggested. Therefore, we determined the renal extraction ratios of NT-proBNP and its bioactive coproduct brain natriuretic peptide (BNP) at rest and during exercise. In addition, the cerebral ratios were evaluated. Ten young healthy men were investigated at baseline, during moderate cycle exercise (heart rate: 140, Borg scale: 14-15), and in the recovery with BNP and NT-proBNP measured from the brachial artery and the jugular and renal veins, and the renal and cerebral extraction ratios (Ext-Ren and Ext-Cer, respectively) were calculated. Cardiac output, stroke volume, heart rate, mean arterial pressures, and estimated glomerular filtration were determined. BNP and NT-proBNP were extracted by the kidneys but not by the brain. We observed no effect of exercise. The mean values (+/- SE) of Ext-Ren of NT-proBNP were similar (0.19 +/- 0.05, 0.21 +/- 0.06, and 0.12 +/- 0.03, respectively) during the three sessions (P > 0.05). Also the Ext-Ren of BNP were similar (0.18 +/- 0.07, 0.15 +/- 0.11, and 0.14 +/- 0.06, respectively; P > 0.05). There were no significant differences between Ext-Ren of BNP and NT-proBNP during the three sessions (P > 0.05). The Ext-Cer of both peptides varied insignificantly between -0.21 +/- 0.15 and 0.11 +/- 0.08. The renal extraction ratio of both BNP and NT-proBNP is approximately 0.15-0.20. There is no cerebral extraction, and short-term moderate exercise does not affect these values. Our findings suggest that the kidneys extract BNP and NT-proBNP to a similar extent in healthy young men.

[Elevated alanine aminotransferase in a four-year-old as an early sign of autoimmune hepatitis].

A four-year-old girl was admitted to a paediatric clinic with a palpable lymph node and elevated alanine aminotransferase (ALT) and weak positive smooth muscle cell antibodies (SMA). Liver biopsy was never done and three months later she was referred with persistent ALT elevation. Eleven years later a dermatologist recognized spider naevi. Autoimmune hepatitis was confirmed by elevation of ALT, immunoglobulin G and positive SMA and a liver biopsy showed cirrhosis and chronic hepatitis. Children with elevated ALT at repeated measurements should be thoroughly examined if no obvious reason is present.

Maintained cerebral and skeletal muscle oxygenation during maximal exercise in patients with liver cirrhosis.

BACKGROUND/AIMS: In cirrhotic patients, insufficient redistribution of blood from splanchnic organs to the central circulation could limit blood supply to skeletal muscles and the brain during exercise. METHODS: Eight cirrhotic patients performed incremental cycling to exhaustion (74 (49-123) W; median with range). RESULTS: Heart rate increased from 68 (62-88)beats/min at rest to 142 (116-163)beats/min, cardiac output from 5.1 (3.3-7.2) to 12.9 (8.5-15.9)l/min, and mean arterial pressure from 89 (75-104) to 115 (92-129)mmHg (P<0.05), while the indocyanine green elimination determined hepatosplanchnic blood flow declined from 0.97 (0.55-1.46) to 0.62 (0.36-1.06)l/min (P<0.05). As assessed by near-infrared spectrophotometry, cerebral oxygenation (NIRS) was 61% (48-85%) and increased to 72% (57-86%) during exercise (P<0.05). The NIRS determined oxygenation of the vastus lateralis muscle also increased: the concentrations of oxygenated haemoglobin by 5.9 (0.57-9.47)micromol/l, deoxygenated haemoglobin by 7.2 (1.8-12.0)micromol/l, and thus total haemoglobin by 12.1 (3.6-21.5)micromol/l (P<0.05). CONCLUSIONS: In patients with cirrhosis, exercise reduces hepatosplanchnic blood flow, while O(2) supply to muscle and brain appears to increase indicating that blood redistribution from splanchnic organs does not limit blood flow to working muscles and the brain.

Splanchnic circulation and metabolism in patients with acute liver failure.

Acute liver failure is associated with mortality of around 50%. The aim of the present studies was to examine the circulatory and metabolic state of the splanchnic region in acute liver failure. This had not been studied previously and it could be expected that improved understanding of the pathophysiology of acute liver failure could lead to improved therapy. Hepatic plasma flow was estimated in patients with acute liver failure after development of hepatic encephalopathy grade III, by the use of liver vein catheterization and continuous infusion of sorbitol. The method was evaluated against the prerequisites of Fick's principle. Hepatic plasma flow could be estimated with sorbitol but not in all patients and the standard error of the estimated hepatic blood flow was higher than in other patient groups. In 20 patients with acute liver failure, mean hepatic blood flow was increased. At the same time, the systemic and the peripheral hemodynamics were examined. The ratio hepatic blood flow/cardiac output was increased in many patients. Lower extremity blood flow was within normal limits. Thus, low systemic vascular resistance index in acute liver failure was likely to be a consequence of vasodilatation in the muscular resistance vessels and, in particular, in the splanchnic resistance vessels. Intervention with high-volume plasmapheresis changed systemic and splanchnic hemodynamics differently, suggesting that the splanchnic vasodilatation in liver failure may by caused by a specific mechanism different from the one that leads to peripheral vasodilatation. Infusion of dopamine increased mean arterial pressure, cardiac output, and hepatic blood flow in acute liver failure. The splanchnic exchange of substrates for oxidative metabolism was examined. Splanchnic oxygen consumption was increased. The ratio splanchnic oxygen consumption/systemic oxygen consumption indicated that 1/3 of the oxygen used in the whole body in acute liver failure was used in the splanchnic region. The splanchnic metabolism of fuel substrates was abnormal. Lactate and pyruvate was released and there were no detectable gradients of free fatty acids or of the sum of amino acids. There was a small release of ketone bodies. The data suggested that the energy needs of the failing liver was covered by intracellular fat. The hypothesis of splanchnic tissue hypoxia was examined from different approaches. The normal hepatic venous oxygen saturation, the splanchnic release of both lactate and pyruvate, and a normal hepatic venous pyruvate/lactate ratio in the presence of low acetoacetate/hydroxybutyrate ratio rather indicated high substrate turnover than splanchnic tissue hypoxia. Amino acid and ammonia metabolism was examined. It was observed that arterial ammonia concentration measured after institution of mechanical ventilation was associated with cerebral herniation 1-5 days later. The background for hyperammonemia was that ammonia was released from the splanchnic circulation. The data implied that glutamine was deamidated in the gut and alanine and ammonia was released into the portal vein as during normal circumstances. Then due to severely decreased hepatic function the liver was unable to remove ammonia and alanine as it normally would. Further, the data implied that urea synthesis was impaired. Exchange of ammonia in muscle tissue was studied in 7 patients with acute liver failure and muscle tissue seems to play a major role in ammonia detoxification in acute liver failure. Treatment with high-volume plasmapheresis decreased arterial ammonia, which was likely due to increased urea production or stimulation of glutamine synthesis in muscle tissue. These findings add to our understanding of the pathophysiology and have implications for the management of acute liver failure.

Splanchnic metabolism in acute liver failure and sepsis.

PURPOSE OF REVIEW: A number of papers have suggested that the splanchnic circulation and oxidative metabolism are compromised in critical illness. This review discusses this hypothesis and outlines the recent advances in the understanding of splanchnic metabolism with special focus on acute liver failure and hyperdynamic sepsis. RECENT FINDINGS: Splanchnic blood flow, oxygen delivery, and consumption are increased in both acute liver failure and sepsis. The capability of the liver to extract oxygen, even under extreme conditions, renders the liver less prone to hypoxia. A common feature of acute liver failure and sepsis is a hypermetabolic state with enhanced glycolysis and production of lactate and pyruvate. Human studies on other features of intermediary metabolism are sparse, but there are indications that several intermediary processes are severely compromised in patients with acute liver failure, whereas these processes are maintained in sepsis. SUMMARY: There is increasing evidence that both acute liver failure and sepsis are accompanied by a hypermetabolic state in the hepatosplanchnic area, characterized by enhanced glycolysis and hyperlactatemia. This should not be rigorously interpreted as an indication of hypoxia. In fact, clinically important splanchnic hypoxia may be a relatively uncommon phenomenon in such patients.