Shakuntala Krishnamurthy

Cholescintigraphic measurement of liver function: how is it different from other methods?

To carry out the complex synthetic (albumin) and excretory (bilirubin) functions, the liver has a unique structure with many different types of cells (hepatocytes, Kupffer cells, stellate cells, cholangiocytes, macrophages) and architecture (endothelial space, space of Disse, canaliculi). Assessment of liver function is usually made indirectly by measurement of its products circulating in blood. Liver function is carried out through release of small protein molecules that bind to their specific receptors, which upon activation release transporter proteins that either stimulate or inhibit gene expression. Liver physiology is reviewed briefly here to emphasize the unique features of measuring cell function directly with cholescintigraphy. Liver function can be divided into four phases: (1) uptake, (2) metabolism, (3) conjugation, and (4) excretion. Uptake of substrates (like bilirubin, or Tc-HIDA) takes place along the basolateral border of the hepatocyte facilitated by NTCP (see Appendix), OATP, MRP, and the Na/K ATPase pump located on the plasma membrane [1]. After uptake, the substrate is metabolized via hydroxylation during phase II. During phase III, conjugation takes place as the products are converted into monoand diglucuronides, which are then excreted into bile canaliculi during phase IV [1]. Canalicular excretion is controlled by BSEP, MDR, OATP, and MRP. Elevation of serum enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) indicates plasma membrane rupture and cell death, but does not reveal much about changes that take place within the cell during substrate transit through all four phases [2]. Uptake along the basolateral border (phase I) usually represents first-pass hepatic extraction fraction and can be measured by applying deconvolutional analysis using heart as the input and liver as the output. Deconvolutional analysis accounts for both intrahepatic blood pool and recirculation from other compartments. Derangement of the basolateral border reduces uptake and hence hepatic extraction fraction. Intracellular transit during phases II, III, and IV is measured as excretion half-time [3]. In many diseases there can be discordance between uptake and intracellular transit. For example, uptake remains normal for some time whereas intracellular transit becomes abnormal immediately after experimental ligation of the common bile duct [4]. In patients with acute common bile duct obstruction due to gallstone, hepatic extraction fraction remains normal for up to 24–48 h but excretion half-time rises to infinity almost immediately [5]. Measurement of hepatic extraction fraction and excretion half-time directly from the liver cells enables assessment of the severity of the liver disease [6]. In this issue of the journal, Veteläinen et al. report on a study in which they used Tc-mebrofenin, a HIDA analogue, to measure in rats the functional changes that take place in liver. They induced fatty liver by feeding rats with a methionineand choline-deficient diet and showed a strong correlation of liver uptake and excretion with severity of inflammation (elevation of plasma and hepatic TNF-α) and altered synthetic function [7]. Studies were obtained before and 1, 3, and 5 weeks following introduction of the diet. Cirrhosis is a continuum that begins as fatty infiltration (steatosis), progresses to inflammation (steatohepatitis) and fibrosis (cirrhosis), and often ends as hepatocellular carcinoma (Fig. 2). Cirrhosis involves participation by hepatocytes, Kupffer cells, stellate cells, and macrophages. Kupffer cells and macrophages are located in the endothelial space, stellate cells in the space of Disse, and cholangioles in the bile ducts, and all are well separated from hepatocytes (Fig. 1). Stellate cells play a crucial role in This editorial commentary refers to the article http://dx.doi.org/10.1007/s00259-006-0125-3.

Cholecystokinin and morphine pharmacological intervention during 99mTc-HIDA cholescintigraphy: A rational approach

Pharmacological intervention with either cholecystokinin-8 (CCK-8) or morphine during 99mTc- hepatoiminodiacetic acid (HIDA) cholescintigraphy is required primarily for the assessment of the diseases affecting the gallbladder, the common bile duct, or the sphincter of Oddi. For imaging, the patient should be prepared by an overnight fast, or with 4 hours of minimum fast. Pre-emptying with CCK-8 is probably undesirable and should either be avoided or one should wait for at least 4 hours after CCK-8 to begin the 99mTc-HIDA study to achieve higher specificity of the test for acute cholecystitis. When he gallbladder is not observed by 60 mins in a clinical setting of acute cholecystitis, a dose of 0.04 mg/kg of morphine is administered intravenously and imaging continued for an additional 30 mins. Nonvisualization of the gallbladder by 90 mins with morphine in an appropriate clinical setting is diagnostic for acute cholecystitis. When the gallbladder is not observed by 60 min but is seen with morphine administered after 60 mins, a positive diagnosis of abnormal gallbladder function can be made. When the gallbladder is observed in a clinical setting of biliary pain or chronic calculous or acalculous cholecystitis, CCK-8 at a dose rate of 3.3 ng/kg/min is infused intravenously for 3 mins (10 ng/kg/3 min) for the measurement of the ejection fraction. An ejection fraction value of less than 35% is indicative of calculous or acalculous chronic cholecystitis. The gallbladder emptying is directly related to the total number of cholecystokinin receptors in the smooth muscle. The ejection fraction can be controlled to any desired level simply by controlling the dose rate or the duration of infusion of CCK-8. Morphine and other opiate metabolites circulate for many hours in blood and act on the sphincter of Oddi and decrease the gallbladder ejection fraction. Careful drug history, especially that of opiates, is very critical in all subjects with a low ejection fraction before assigning an abnormality to the gallbladder motor function.

Characterization of basal hepatic bile flow and the effects of intravenous cholecystokinin on the liver, sphincter, and gallbladder in patients with sphincter of Oddi spasm

The major objectives of this project were to establish the pattern of basal hepatic bile flow and the effects of intravenous administration of cholecystokinin on the liver, sphincter of Oddi, and gallbladder, and to identify reliable parameters for the diagnosis of sphincter of Oddi spasm (SOS). Eight women with clinically suspected sphincter of Oddi spasm (SOS group), ten control subjects (control group), and ten patients who had recently received an opioid (opioid group) were selected for quantitative cholescintigraphy with cholecystokinin. Each patient was studied with 111–185xa0MBq (3–5xa0mCi) technetium-99m mebrofenin after 6–8xa0h of fasting. Hepatic phase images were obtained for 60xa0min, followed by gallbladder phase images for 30xa0min. During the gallbladder phase, 10xa0ng/kg octapeptide of cholecystokinin (CCK-8) was infused over 3xa0min through an infusion pump. Hepatic extraction fraction, excretion half-time, basal hepatic bile flow into the gallbladder, gallbladder ejection fraction, and post-CCK-8 paradoxical filling (>30% of basal counts) were identified. Seven of the patients with SOS were treated with antispasmodics (calcium channel blockers), and one underwent endoscopic sphincterotomy. Mean (±SD) hepatic bile entry into the gallbladder (versus GI tract) was widely variable: it was lower in SOS patients (32%±31%) than in controls (61%±36%) and the opioid group (61%±25%), but the difference was not statistically significant. Hepatic extraction fraction, excretion half-time, and pattern of bile flow through both intrahepatic and extrahepatic ducts were normal in all three groups. Gallbladder mean ejection fraction was 9%±4% in the opioid group; this was significantly lower (P<0.0001) than the values in the control group (54%±18%) and the SOS group (48%±29%). Almost all of the bile emptied from the gallbladder refluxed into intrahepatic ducts; it reentered the gallbladder after cessation of CCK-8 infusion (paradoxical gallbladder filling) in all eight patients with SOS, but in none of the patients in the other two groups. Mean paradoxical filling was 204% (±193%) in the SOS group and less than 5% (P<0.05) in both the control and the opioid group. After treatment, six of the SOS patients had complete pain relief and one, partial pain relief. The basal tonus of the sphincter is variable in patients with SOS, and allows relatively more of the hepatic bile to enter the GI tract than the gallbladder. Due to simultaneous contraction of the sphincter and gallbladder in response to CCK-8, most of the bile emptied from the gallbladder refluxes into intrahepatic ducts, and reenters the gallbladder immediately after cessation of hormone infusion. The characteristic features of gallbladder filling, emptying, and paradoxical refilling with cholecystokinin provide objective parameters for noninvasive diagnosis of SOS by quantitative cholescintigraphy.

Hazards of formulating new theories about gallbladder (GB) function based on ultrasound volume data.

Hazards of Formulating New Theories About Gallbladder (GB) Function Based on Ultrasound Volume Data

Development and validation of a comprehensive new hepatobiliary software. Part II: Segmental liver function.

ObjectiveThis study was undertaken to develop comprehensive new hepatobiliary software to quantify segmental and lobar liver function and to obtain FDA approval. MethodsHepatobiliary software written on JAVA platform and loaded on to a PC accepts 99mTc-HIDA dicom image data transferred from a &ggr; camera. Liver boundary was determined by threshold-based auto edge detection and liver height at right midclavicular (RMCL) line. Geometric mean area of the physiologic right lobe, physiologic left lobe and total liver area were measured. Segmental liver function was determined using the 5th minute frame as the default (100%). ResultsIn 24 control participants, mean (±SD) liver height at RMCL was 14.7±0.12u2009cm. Geometric mean area of the physiologic right lobe was 116±3u2009cm2, left lobe 96±4u2009cm2, and total liver area 212±3u2009cm2. Right upper lobe (segments 7 and 8) contributed 31±0.7%, right lower lobe (segments 5 and 6) 34±0.6%, left medial (segments 4A and 4B) 24±1%, left lateral (segments 2 and 3) 10±2%, and caudate lobe (segment 1) 1±0.02% of total liver function. In 23 patients, contrast three-dimensional computerized tomographic volume of the right lobe was 1194±419u2009ml, left lobe 434±221u2009ml, and total liver volume 1628±490u2009ml. Right lobe area was120±30u2009cm2, left lobe (plus caudate) 88±29u2009cm2 with total liver area of 208±51u2009cm2. Right upper lobe (segments 7 and 8) contributed 33±10%, right lower lobe (segments 5 and 6) 34±7%, left medial (segments 4A and 4B) 23±6%, left lateral (segments 2 and 3) 9±3%, and caudate lobe (segment 1) 1±0.4% of total liver function. There was good correlation of RMCL height, and area of right lobe and total liver with computerized tomographic liver volume. Correlation of percentage volume with percentage function was excellent. ConclusionNew FDA approved software provides quantitative assessment of segmental, lobar, and total liver size and function from a planar 99mTc-HIDA cholescintigraphy and may enable universal standardization in nuclear hepatology. Quantification may aid surgeons in the determination of the amount of tissue resection during liver surgery.

Liver and Spleen Function

The liver is the largest organ and carries out the most complex biological functions in the body. It secretes bile, synthesizes proteins, metabolizes nutrients, hormones, and drugs, and detoxifies noxious endogenous and exogenous substrates. To accomplish all of these functions, the liver is located centrally in the body and endowed with well-designed architecture with a generous amount of blood supply. Secretion of bile is one of many important liver functions, and bile promotes digestion and absorption of essential nutrients; it also serves as a vehicle to get rid of biological waste products from the body. The biliary tree is designed not only for continuous bile secretion and flow, but also for periodic bile storage and discharge (gallbladder) at the time when food enters the small intestine. The spleen carries out many functions whose importance has been recognized only recently. This chapter will discuss the various functions of these two organs.

Imaging and Quantification of Hepatobiliary Function

The liver is one of the most frequently imaged organs in the body, using ultrasound, CT, MRI, or scintigraphy. The first three imaging techniques depend upon morphological changes to detect disease, whereas scintigraphy uses both morphological and physiological changes to discover liver pathology. Since physiological changes usually precede morphological alterations by several weeks or months, there is great potential for early diagnosis by scintigraphy, well before irreversible functional changes take place. Once very popular, imaging with radiocolloids now has been almost completely replaced by quantitative hepatobiliary functional imaging with Tc-99m HIDA [1].

Diseases of the Gallbladder

Liver and gallbladder diseases are two of the most common digestive system problems around the world [1]. In the United States, there are about 20.5 million people with gallbladder disease, with an estimated annual cost for medical care of more than 6.4 billion dollars [2]. Gallstones account for the majority of gallbladder problems. Women are affected two to three times as frequently as men [3]. Race, heredity, gender, age, and obesity are some of the important known risk factors for gallstones (Table 9.1.1). Between the ages 60 and 74, the prevalence of gallbladder disease is as high as 25.3% in men and 33.1%% in women (Table 9.1.2), and it is relatively more common among the Mexican Americans (Table 9.1.3). The highest rate among the Americans is found in the Pima Indians of Arizona [4]. By the teenage years, as many as 10–13% of Pima Indian girls develop lithogenic bile, and by 35–44 years, about 71% develop gallstones. Almost 90% of Pima Indian women over the age of 65 develop gallbladder disease, and the prevalence is much higher than in Pima Indian men.

Malignant Liver Lesions

The liver is a common site for both primary and metastatic malignant lesions. Although the metastatic lesions are the most common, primary malignancies like hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) have become increasingly more common in recent years in the United States [1]. HCC arises from the hepatic parenchymal cells, the hepatocytes, and CC from the cells lining the major bile ducts and gallbladder, the cholangiocytes. In Asian countries like China, Taiwan, and Japan, HCC is one of the three most common causes of death due to malignancy. HCC has a serum marker in the form of α-fetoprotein, and no such marker exists for CC. Gallium-67 citrate, which has been an imaging agent for HCC over the years, still remains popular in places where F-18 fluorodeoxyglucose (F-18 FDG) is not readily available. A filling defect on a radiocolloid liver scan (Fig. 12.1.1) associated with intense Ga-67 uptake (Fig. 12.1.2) and increased serum α-fetoprotein in a patient is more likely to be HCC than any other type of malignancy. F-18 FDG shows avidity for CC, HCC, metastatic lesions, and abscesses. Being a common imaging agent for many different types of liver lesions, F-18 FDG imaging provides no specificity for any one particular type of malignancy.

Pediatric Nuclear Hepatology

The liver and biliary system develops from a bi-lobed (cephalic and caudal) endodermal bud that sprouts along the ventral surface of the distal end of the foregut at its junction with the midgut. The cephalic bud divides into two branches, which later form the right and left lobes of the liver. The caudal bud gives rise to biliary tract and the gallbladder (Fig. 11.1.1, Chap. 1). The biliary tract starts first as a patent tubular structure, but turns into a solid core during early intrauterine life through the proliferation of epithelial cells. After recanalization of the solid core by 12–14 weeks, bile secretion begins and flows into the small intestine. Most of the congenital abnormalities of the biliary tract are due to either failure of recanalization of the ducts (biliary atresia) or faulty recanalization with cystic dilatation of intrahepatic (Caroli’s disease) and extrahepatic ducts (choledochal cyst).