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The thirsty liver: dynamic T₁ mapping after fluid intake in healthy volunteers

Ferenc E. Mozes¹, Emmanuel A. Selvaraj¹, Michael Pavlides^1,2, Matthew D. Robson^1,3, and Elizabeth M. Tunnicliffe¹
¹OCMR, RDM Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom, ²Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom, ³Perspectum Diagnostics Ltd., Oxford, United Kingdom

Synopsis

Non-alcoholic fatty liver disease is on the rise and liver biopsies used to diagnose it need to be replaced by non-invasive methods such as T₁ mapping. Guidance for MRI scans allow for free water consumption before scans, increasing measurement variability. We therefore aimed to assess the effect of hydration on liver T₁ by acquiring serial shMOLLI T₁ maps after participants drank 1 litre of isotonic water. As water passed through the stomach and small intestines it first reached the portal circulation and later the systemic circulation, causing an increase in liver T₁ followed by an increase in spinal muscle T₁.

Introduction

Non-alcoholic fatty liver disease (NAFLD) has a wide prevalence both in Western countries and worldwide (1). While it can be asymptomatic for a long time and never progress to more severe stages, its natural progression may lead to cirrhosis, liver failure, and hepatocellular carcinoma. The reference standard for diagnosing NAFLD is liver biopsy (2) which is invasive and carries a risk of complications (3). Non-invasive imaging biomarkers, such as T₁ mapping are emerging as potential alternatives to liver biopsy in staging liver fibrosis and disease activity in NAFLD (4). However, T₁ mapping is confounded by a number of factors related to disease (iron concentration (5), fat fraction (6)), technical limitations (B₀ inhomogeneities (7)) and diurnal physiological changes in the liver (glycogen concentration (8)). Current guidance for liver T₁ mapping scans can allow free consumption of water before the examination; brain T₁ has been shown to depend on hydration status (9). We therefore aimed to explore the dynamic response of liver T₁ to fluid consumption.

Methods

Six healthy volunteers (1 female, mean age: 30±3 years) had shMOLLI T₁ (10) maps collected on a 3 T Siemens Prisma scanner (Erlangen, Germany). Participants underwent 4 hours of food fasting and 1 hour of water fasting prior to the study. After baseline measurements had been acquired, participants were taken out of the scanner and asked to drink 1 litre of isotonic water, then they returned to the scanner where serial T₁ measurements were carried out every 5 minutes for at least 1 hour. T₁ values of the liver and spinal erector muscles were recorded to assess the effect of hydration through the portal circulation and the systemic circulation. Paired t-tests were used to compare shMOLLI T₁ values before and after water ingestion (at the peak of the T₁ response). Liver and muscle were modelled as a first-order system. The ingested water passing through the stomach, absorbed in the small intestines and parts of it released in the portal circulation was considered as a pulse input function (Figure 1). In this case the time response of the liver in T₁ is described by: $$T_1(t)=K_l(1-e^{-\frac{t-\delta}{\tau_l}})u(t-\delta)-K_l(1-e^{-\frac{t-\delta-\Delta}{\tau_l}})u(t-\delta-\Delta)+T_{1,0}$$ where u(t) is the Heaviside step function. The acquired T₁ time series were fitted to this equation to determine K_l (a gain factor related to the magnitude of the T₁ change), $$$\tau_l$$$ (the time constant of the liver, determining the rate of water uptake), $$$\delta$$$ (the delay between ingesting the water and the initial upslope in T₁), $$$\Delta$$$ (the length of the pulse input) and T_1,0 (the T₁ of the liver in the absence of the water input). The time response of muscle T₁ to a half-trapezoidal input function through the systemic circulation was: $$T_1(t)=K_m(\tau_m-t-\tau_me^{-\frac{t-\delta_1}{\tau_m}}+\delta_1)u(t-\delta_1)-K_m(\tau_m-t-\tau_me^{-\frac{t-\delta_2}{\tau_m}}+\delta_2)u(t-\delta_2)+T_{1,0}$$ Muscle T₁ values were fitted to this equation to determine K_m, $$$\tau_m$$$, $$$\delta_1$$$ (delay between ingesting the water and the initial upslope in muscle T₁) and $$$\delta_2$$$ (duration of the upslope).

Results

All subjects consumed the litre of fluid within 4 minutes. Figure 2 shows the time evolution of liver and muscle T₁ in one participant. An increase in liver T₁ from baseline was observed in all participants after water ingestion (p=0.003). Mean baseline liver T₁ was 651±65 ms (range: 575-724 ms), mean time constant was 25±15 minutes (range 4-39 minutes), mean pulse length was 26±7 minutes (range: 17-34 minutes) and mean initial delay time was 10±6 minutes (range: 3.3-19 minutes). Figure 3 summarises the models derived for all participants. Liver T₁ peaked at 36±5 minutes on average (range: 27 to 39 minutes) reflecting an observed average increase of 67±30 ms. Mean baseline muscle T₁ was 1012±36 ms (range: 968-1062 ms), mean time constant was 5±8 minutes (range: 0.06 - 21 minutes), mean delay until upslope in T₁ was 19±8 minutes (range: 7-29 minutes) and mean upslope duration was 36±20 minutes (range: 9-68 minutes).

Discussion and conclusion

We have shown that liver T₁ increased after the administration of 1 litre of isotonic water in fasting participants. Water absorbed by the small intestines entered the portal circulation first, increasing the extracellular water volume of the liver before it reached the systemic circulation – as suggested by the longer upslope delay and duration of muscle T₁. The variability observed in the delay times of the model may be explained by the gut’s contribution to reaching water homeostasis. This model of the liver’s dynamic response to fluid intake could be useful in the determination of the timing of future metabolic experiments. Our measurements captured the transient changes in the liver as they would naturally occur in participants of clinical liver MRI studies who are allowed to freely consume water prior to their scans. In addition, it is possible that NAFLD patients who have undergone bariatric surgery will have different rates of gastric emptying affecting the time of water release from the gut, and ultimately resulting a different liver T₁ evolution than it was found in healthy volunteers. Based on this assumption and the fact that the magnitude of observed T₁ changes is comparable to an increase in T₁ due to an increase of an Ishak fibrosis stage (5), clear fasting instructions for liver MRI study participants will ensure reproducible measurements.

Acknowledgements

No acknowledgement found.

References

1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M: Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. J Hepatol 2016; 64:73–84.

2. European Association for the Study of the Liver (EASL) EA for the S of D (EASD), EA for the S of O (EASO), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO): EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease. Obes Facts 2016; 9:65–90.

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Figures

Figure 1: Schematic of the water transitioning through the digestive system. Green arrows mark the path of the water from the oesophagus through the stomach to the small intestines at which point it is considered as a pulse input function to the intestines and the liver. Once water reached the liver, it is collected through the hepatic veins and drained into the IVC, entering the systemic circulation and reaching other organs as a saturated ramp function.

Figure 2: Time evolution of liver T₁ (a) and spinal muscle T₁ (c) in one participant. $$$\Delta$$$ and $$$\delta$$$ are the duration of the upslope and the initial delay time of liver T₁ evolution, $$$\delta_1$$$ is the initial delay in muscle T₁ evolution. Water reached systemic circulation later than portal circulation, as indicated by the longer delay in muscle T₁ evolution ($$$\delta<\delta_1$$$). T₁ maps of the initial, maximal absorption and final stages are also shown (b). Data at T=0 s correspond to baseline measurements and error bars represent standard deviations.

Figure 3: Fitted models of all participants’ liver T₁ time evolution (a) and spinal erector muscle T₁ evolution (b). The six different dynamics showed a good level of similarity between participants.

Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)

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