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Cerebral Blood Flow and Metabolism in Hepatic Encephalopathy—A Meta-Analysis

      Hepatic Encephalopathy (HE) is associated with abnormalities in brain metabolism of glucose, oxygen and amino acids. In patients with acute liver failure, cortical lactate to pyruvate ratio is increased, which is indicative of a compromised cerebral oxidative metabolism. In this meta-analysis we have reviewed the published data on cerebral blood flow and metabolic rates from clinical studies of patients with HE. We found that hepatic encephalopathy was associated with reduced cerebral metabolic rate of oxygen, glucose, and blood flow. One exemption was in HE type B (shunt/by-pass) were a tendency towards increased cerebral blood flow was seen. We speculate that HE is associated with a disturbed metabolism—cytopathic hypoxia—and that type specific differences of brain metabolism is due to differences in pathogenesis of HE.

      Abbreviations:

      ALF (Acute Liver Failure), CBF (Cerebral Blood Flow), CMR (Cerebral Metabolic Rate), HE (Hepatic Encephalopathy), ICH (Intracranial Hypertension), MHE (Minimal Hepatic Encephalopathy), MRI (Magnetic Resonance Imaging), OHE (Overt Hepatic Encephalopathy), pcMRI (Phase-Contrast MRI), PCS (Portocaval Shunt)

      Keywords

      During Hepatic Encephalopathy (HE) the deterioration of brain function is accompanied by alterations in brain perfusion and energetics. Over several decades, several studies have focused on this pathophysiological aspect. The regulation of cerebral perfusion is essential in supporting the metabolic requirements for normal brain function. Under normal physiological conditions the global Cerebral Blood Flow (CBF) is kept almost constant during variations in systemic blood pressure—the cerebral autoregulation.
      • Lassen NA.
      Autoregulation of cerebral blood flow.
      Furthermore, during normal brain function the regional changes in neuronal activity are matched with a tight regulation of the regional CBF in the so called neurovascular unit.
      • Iadecola C
      • Nedergaard M.
      Glial regulation of the cerebral microvasculature.
      Several mechanisms are involved in this, including the myogenic response (the Bayliss effect)
      • Bayliss WM
      On the local reactions of the arterial wall to changes of internal pressure.
      that couples hydrostatic pressure with vascular wall tone as well as the neurovascular coupling of metabolic supply and demand that acts through numerous and redundant mediators.
      • Iadecola C.
      The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease.
      Given the multifactorial pathophysiology of HE and the involvement several mechanisms that are directly or indirectly associated with perfusion and energy utilization, it is not surprising that patients with HE suffer from dysmetabolism and dysperfusion of the brain. For example, cerebral ammonium toxicity has experimentally been shown to affect extracellular potassium buffering,
      • Rangroo Thrane V
      • Thrane AS
      • Wang F
      • et al.
      Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering.
      adenosine tone,
      • Bjerring PN
      • Dale N
      • Larsen FS.
      Acute hyperammonemia and systemic inflammation is associated with increased extracellular brain adenosine in rats: a biosensor study.
      glutamate signalling,
      • Monfort P
      • Munoz MD
      • El Ayadi A
      • Kosenko E
      • Felipo V.
      Effects of hyperammonemia and liver failure on glutamatergic neurotransmission.
      lactate homeostasis,
      • Bosoi CR
      • Rose CF.
      Elevated cerebral lactate: implications in the pathogenesis of hepatic encephalopathy.
      and microglia activation,
      • Butterworth RF
      The liver-brain axis in liver failure: neuroinflammation and encephalopathy.
      which all represent potential points of interference with normal CBF regulation. With this literature review we summarize the published data on CBF and brain metabolism in patients with HE with special focus on: (1) the effect of HE on the global absolute CBF (mL of blood/100 g brain tissue * min) and (2) the cerebral metabolic rates of oxygen (CMRO2 (mL of oxygen/100 g brain tissue * min)) and glucose (CMRglc (µmol of glucose/100 g brain tissue * min)).

      Methods

      We performed our literature search using the terms “hepatic encephalopathy” and “cerebral blood flow”, “brain blood flow”, “fulminant liver failure”, or “cerebral metabolic rate”. The final search was completed in January 2018, using the following search engines: MEDLINE, Scopus, Web of Science, and Embase. From the publications, we extracted estimates of CBF and cerebral metabolic rates. Our inclusion criteria were: human data on absolute measurements of CBF in patients with HE. Analyses were done in the statistical software R ver. 3.2.1 (R Foundation for Statistical Computing, Vienna, Austria) using the package ‘metafor’. We calculated standardised mean differences of CBF and metabolic rates and fitted random-effects models as a conservative effect measure. I2 was used as a marker of heterogeneity. We undertook subgroup analyses based on the aetiology of HE and the method of CBF measurements. The majority of the studies reported results expressed in means ± standard deviation. Where median (range) values were used we accepted the median as an approximation of the sample mean and estimated the standard deviation as (maximum–minimum)/4.

      Results

      Our literature search resulted in 345 individual publications. Of these, 80 papers contained human original data. After exclusion of publications with case reports or only relative changes in CBF, we finally included 27 papers with absolute measurements of CBF in patients with HE. Of these, 16 described comparisons between patients with HE (minimal and/or overt) and controls (healthy subjects and/or cirrhotic patients without HE) allowing us to estimate the standardized mean differences. 14 studies also reported data on CMRO2 and CMRglc. The 27 included studies are listed in Table 1 and the CBF data from each study in Table 2.
      Table 1The 27 Included Studies in the Meta-Analysis.
      AuthorYearJournalHE typeMethod
      Zheng
      • Zheng G
      • Lu H
      • Yu W
      • et al.
      Severity-specific alterations in CBF, OEF and CMRO2 in cirrhotic patients with hepatic encephalopathy.
      2017European Journal of RadiologyCirrhosis OHEpcMRI
      Zheng
      • Zheng G
      • Zhang LJ
      • Cao Y
      • Lu GM.
      Venous blood ammonia can be associated with cerebral blood flow in hepatic encephalopathy.
      2013European Journal of RadiologyMHEMRI Arterial Spin
      Strauss
      • Strauss GI
      • Knudsen GM
      • Kondrup J
      • Moller K
      • Larsen FS.
      Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure.
      2001GastroenterologyALFKety-Schmidt 133-Xe
      Almdal
      • Almdal TP
      • Sorensen TI.
      Incidence of parenchymal liver diseases in Denmark, 1981 to 1985: analysis of hospitalization registry data. The Danish Association for the Study of the Liver.
      1989Scand J GastroenterologyALFKety-Schmidt 133-Xe
      Aggarwal
      • Aggarwal S
      • Yonas H
      • Kang Y
      • et al.
      Relationship of cerebral blood flow and cerebral swelling to outcome in patients with acute fulminant hepatic failure.
      1991Transpl ProcALFKety-Schmidt 133-Xe
      Wendon
      • Wendon JA
      • Harrison PM
      • Keays R
      • Williams R.
      Cerebral blood flow and metabolism in fulminant liver failure.
      1994HepatologyALFKety-Schmidt 133-Xe
      Durham
      • Durham S
      • Yonas H
      • Aggarwal S
      • Darby J
      • Kramer D.
      Regional cerebral blood flow and CO2 reactivity in fulminant hepatic failure.
      1995JCBFALFKety-Schmidt 133-Xe
      Jalan
      • Jalan R
      • Olde Damink SW
      • Deutz NE
      • Hayes PC
      • Lee A
      Restoration of cerebral blood flow autoregulation and reactivity to carbon dioxide in acute liver failure by moderate hypothermia.
      2001HepatologyALF-ICHN2O
      Jalan
      • Jalan R
      • Olde Damink SW
      • Hayes PC
      • Deutz NE
      • Lee A.
      Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow.
      2004GastroenterologyALF-ICHN2O
      Dam
      • Dam G
      • Keiding S
      • Munk OL
      • et al.
      Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake.
      2013HepatologyCirrhosis OHEPET 15-O
      Iversen
      • Iversen P
      • Sorensen M
      • Bak LK
      • et al.
      Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy.
      2009GastroenterologyCirrhosis OHEPET 15-O
      Porro
      • Bianchi Porro G
      • Maiolo AT
      • Della Porta P
      Cerebral blood flow and metabolism in hepatic cirrhosis before and after portacaval shunt operation.
      1969GutPCSN2O
      Zheng
      • Zheng G
      • Zhang LJ
      • Wang Z
      • et al.
      Changes in cerebral blood flow after transjugular intrahepatic portosystemic shunt can help predict the development of hepatic encephalopathy: an arterial spin labeling MR study.
      2012European Journal of RadiologyAfter TIPSMRI Arterial Spin
      Jalan
      • Jalan R
      • Olde Damink SW
      • Ter Steege JC
      • et al.
      Acute endotoxemia following transjugular intrahepatic stent-shunt insertion is associated with systemic and cerebral vasodilatation with increased whole body nitric oxide production in critically ill cirrhotic patients.
      2010Journal of Hepatology1 h after TIPSN2O
      Ahl
      • Ahl B
      • Weissenborn K
      • van den Hoff J
      • et al.
      Regional differences in cerebral blood flow and cerebral ammonia metabolism in patients with cirrhosis.
      2004HepatologyMHEPET 15-O
      Larsen
      • Larsen FS
      • Strauss G
      • Knudsen GM
      • Herzog TM
      • Hansen BA
      • Secher NH.
      Cerebral perfusion, cardiac output, and arterial pressure in patients with fulminant hepatic failure.
      2000Critical Care MedicineALFKety-Schmidt 133-Xe
      Larsen
      • Larsen FS
      • Strauss G
      • Moller K
      • Hansen BA.
      Regional cerebral blood flow autoregulation in patients with fulminant hepatic failure.
      2000Critical Care MedicineALFKety-Schmidt 133-Xe
      Larsen
      • Larsen FS
      • Ejlersen E
      • Strauss G
      • et al.
      Cerebrovascular metabolic autoregulation is impaired during liver transplantation.
      1999TransplantationALFKety-Schmidt 133-Xe
      Philips
      • Philips BJ
      • Armstrong IR
      • Pollock A
      • Lee A.
      Cerebral blood flow and metabolism in patients with chronic liver disease undergoing orthotopic liver transplantation.
      1998HepatologyCirrhosis OHEN2O
      Larsen
      • Larsen FS
      • Ejlersen E
      • Clemmesen JO
      • Kirkegaard P
      • Hansen BA.
      Preservation of cerebral oxidative metabolism in fulminant hepatic failure: an autoregulation study.
      1996Livertransplantation SurgicalALFKety-Schmidt 133-Xe
      Larsen
      • Larsen FS
      • Olsen KS
      • Ejlersen E
      • Hansen BA
      • Paulson OB
      • Knudsen GM.
      Cerebral blood flow autoregulation and transcranial Doppler sonography in patients with cirrhosis.
      1995HepatologyCirrhosis OHEKety-Schmidt 133-Xe
      Lockwood
      • Lockwood AH
      • Yap EW
      • Wong WH.
      Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy.
      1991JCBFLiver diseasePET 15-O
      Testa
      • Testa R
      • Rodriguez G
      • Arvigo F
      • et al.
      Cerebral blood flow and plasma free tryptophan in cirrhotics with and without hepatic encephalopathy.
      1989Ital J Neu SciMHEKety-Schmidt 133-Xe
      Rodriguez
      • Rodriguez G
      • Testa R
      • Celle G
      • et al.
      Reduction of cerebral blood flow in subclinical hepatic encephalopathy and its correlation with plasma-free tryptophan.
      1987JCBFMMHEKety-Schmidt 133-Xe
      James
      • James IM
      • Garassini M.
      Effect of lactulose on cerebral metabolism in patients with chronic portosystemic encephalopathy.
      1971GutCirrhosis OHEKety-Schmidt 133-Xe
      Posner
      • Posner JB
      • Plum F.
      The toxic effects of carbon dioxide and acetazolamide in hepatic encephalopathy.
      1960J Clin InvestCirrhosis OHEKety-Schmidt
      Fazekas
      • Alman RW
      • Ehrmantraut WR
      • Fazekas JF
      • Ticktin HE.
      Cerebral metabolism in hepatic insufficiency.
      1956American Journal of MedicineCirrhosis OHEKety-Schmidt
      ALF: Acute Liver Failure; ICH: Intracranial Hypertension; MHE: Minimal Hepatic Encephalopathy; MRI: Magnetic Resonance Imaging; OHE: Overt Hepatic Encephalopathy; pcMRI: Phase-Contrast MRI; PCS: Portocaval Shunt.
      Table 2Cerebral Blood Flow Estimates From the Included Studies.
      AuthorYearOHEALFShunt (TIPS/PCS)MHECirrhotic controlsHealthy controls
      NCBF mean ± s.d.NCBF mean ± s.d.NCBF mean ± s.d.NCBF mean ± s.d.NCBF mean ± s.d.NCBF mean ± s.d.
      Zheng2017845.3±16.01155.6±7.91467.8±7.33157.1±9.8
      Zheng20131639.0±8.01667.4±11.52052.2±12.02548.8±8.9
      Strauss20011639.0±8.0562.0±11.0863.0±9.0
      Almdal19891231.0±4.0
      Aggarwal19913342.0±19.8
      Wendon19943030.0±14.3
      Durham19952442.0±13.02455.0±10.0
      Jalan20019111.0±16.3
      Jalan20041478.0±9.7
      Dam20131029.1±9.4944.7±6.2
      Iversen2009630.2±2.5648.9±5.1751.0±7.6
      Porro1969897.6±26.8863.8±22.11254.3±9.1
      Zheng2012965.5±17.9960.0±11.0
      Jalan2010967.2±9.6953.2±7.2
      Ahl2004542.4±6.2352.8±11.1
      Larsen2000834.0±16.3
      Larsen20001230.0±9.8
      Larsen19991343.8±10.4
      Philips19981444.0±16.3
      Larsen1996634.0±10.8
      Larsen1995660.8±11.9667.5±13.3
      Lockwood19911151.0±24.01154.0±20.0
      Testa19892042.3±6.91047.5±5.4
      Rodriguez19871842.0±7.01850.0±6.0
      James1971656.0±18.4
      Posner19601839.3±10.91153.0±8.0
      Fazekas19561639.6±8.02047.1±8.1
      Data expressed as means ± standard deviation in the unit of mL blood/100 g*min. ALF: Acute sLiver Failure; MHE: Minimal Hepatic Encephalopathy; OHE: Overt Hepatic Encephalopathy; PCS: Portocaval Shunt; TIPS: Transjugular Intrahepatic Portosystemic Shunt.
      Our meta-analysis revealed a large degree of variation in CBF results across studies (Table 2). By limiting our analysis to the 16 studies that included comparisons between groups we found no clear difference between patients with HE compared with controls (Figure 1). The random-effects analysis showed substantial heterogeneity (I2 = 90.88%). We therefore undertook subgroup analyses based on the type of HE and modality of CBF measurement. These analyses showed that MRI and N2O based methods resulted in higher CBF during HE (Figure 2A) and that HE type B in contrast to type A and C was more likely to results in increased CBF (Figure 2B).
      Figure 1
      Figure 1Random-effects meta-analysis of studies with estimates of standardized mean differences (SMD). Insert: funnel plot. ALF: Acute Liver Failure; Minimal HE: Minimal Hepatic Encephalopathy; OHE: Overt Hepatic Encephalopathy; PCS: Portocaval Shunt; TIPS: Transjugular Intrahepatic Portosystemic Shunt.
      Figure 2
      Figure 2Random-effects subgroup analysis based on the modality of cerebral blood flow measurement (A) and aetiology of hepatic encephalopathy (B).
      The metabolic rates of oxygen were significantly lower in patients with HE (Figure 3), but the analysis demonstrated substantial heterogeneity. The metabolic rate of glucose tended to be lower during HE, but only three studies were available for this comparison.
      Figure 3
      Figure 3Random-effects meta-analysis of cerebral metabolic rates of oxygen (A) and glucose (B).

      Discussion

      Our findings support the current understanding of HE as a metabolic encephalopathy with reduced neuronal activity and hence a reduced CBF and delivery of oxygen and glucose. Generally, we found that the results were characterised by a rather large degree of variation and substantial heterogeneity between studies. Of interest we found that HE due portacaval shunting (type B) was associated to an increased CBF, in contrast to studies of patients with HE of type A and C. This could indicate that the pathogenesis in HE is type specific and that the isolated hyperammonia that is often seen in type B HE leads to vasodilation and hyperperfusion, which also has been observed in animal studies.
      • Bjerring PN
      • Bjerrum EJ
      • Larsen FS.
      Impaired cerebral microcirculation induced by ammonium chloride in rats is due to cortical adenosine release.
      It is also noteworthy that the cerebral metabolic rates tended to be unaltered in type B HE in contrast to the reduced metabolic rates that were seen in type A and C. Since type A and C HE often is seen in patients with multi-organ failure, infections and electrolyte disturbances it is likely that the brain metabolism and blood flow is affected in a multifactorial fashion that leads to reduced neuronal activity and hence reduced blood flow. It is important to stress the fact that we found substantial heterogeneity in our meta-analysis and that most of the studies were done with rather small sample sizes and at different time-points in the disease course. It should also be noted that we were not able to account for the individual arterial partial pressures of carbon dioxide, haemoglobin levels or the type and depth of sedation, which all could represent potential confounding factors.
      One interesting aspect observed in several experimental and clinical studies is cerebral accumulation of lactate
      • Bosoi CR
      • Rose CF.
      Elevated cerebral lactate: implications in the pathogenesis of hepatic encephalopathy.
      ,
      • Witt AM
      • Larsen FS
      • Bjerring PN
      Accumulation of lactate in the rat brain during hyperammonaemia is not associated with impaired mitochondrial respiratory capacity.
      • Bosoi CR
      • Zwingmann C
      • Marin H
      • et al.
      Increased brain lactate is central to the development of brain edema in rats with chronic liver disease.
      • Bjerring PN
      • Larsen FS.
      Changes in cerebral oxidative metabolism in patients with acute liver failure.
      • Bjerring PN
      • Hauerberg J
      • Jorgensen L
      • et al.
      Brain hypoxanthine concentration correlates to lactate/pyruvate ratio but not intracranial pressure in patients with acute liver failure.
      • Chatauret N
      • Zwingmann C
      • Rose C
      • Leibfritz D
      • Butterworth RF
      Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study.
      • Zwingmann C
      • Chatauret N
      • Leibfritz D
      • Butterworth RF.
      Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H–C] nuclear magnetic resonance study.
      and we have previously proposed that the brain is suffering from some kind of cytopathic hypoxia
      • Bjerring PN
      • Larsen FS.
      Changes in cerebral oxidative metabolism in patients with acute liver failure.
      —e.g. a condition with anaerobe metabolism in spite of sufficient delivery of oxygen. This is based on the circumstance that the metabolic abnormalities seem too extensive to simply reflect reduced neuronal activity. Conditions associated with hypoxic metabolism include: (1) ischemia hypoxia due to low perfusion pressure, (2) low oxygen extraction due to low pO2, anaemia, or increased haemoglobin oxygen affinity, (3) arteriovenous shunting, (4) increased diffusion distance or reduced endothelial diffusion area, (5) impaired mitochondrial function, and (6) hypermetabolism. Most of these types of hypoxia can be excluded in HE based on published experimental and clinical data cited above. However dysperfusion in the cerebral microcirculation—for example due to shunting—might be a possible explanation, that to our knowledge has not been thoroughly studied although the hypothesis is far from new.
      • Baldy-Moulinier M
      • Bories P.
      CBF and metabolism in hepatic encephalopathy: effects of acute hyperammoneamia and of L. dopa.
      In conclusion, we have found substantial heterogeneity in the published results on CBF and metabolic rates for oxygen and glucose in patients with HE. However, a general tendency towards reduced flow and metabolism was found.

      Conflicts of interest

      The authors have none to declare.

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