Metabolic dysfunction-associated gallstone disease: expecting more from critical care manifestations

Abstract

About 20% of adults worldwide have gallstones which are solid conglomerates in the biliary tree made of cholesterol monohydrate crystals, mucin, calcium bilirubinate, and protein aggregates. About 20% of gallstone patients will definitively develop gallstone disease, a condition which consists of gallstone-related symptoms and/or complications requiring medical therapy, endoscopic procedures, and/or cholecystectomy. Gallstones represent one of the most prevalent digestive disorders in Western countries and patients with gallstone disease are one of the largest categories admitted to European hospitals. About 80% of gallstones in Western countries are made of cholesterol due to disturbed cholesterol homeostasis which involves the liver, the gallbladder and the intestine on a genetic background. The incidence of cholesterol gallstones is dramatically increasing in parallel with the global epidemic of insulin resistance, type 2 diabetes, expansion of visceral adiposity, obesity, and metabolic syndrome. In this context, gallstones can be largely considered a metabolic dysfunction-associated gallstone disease, a condition prone to specific and systemic preventive measures. In this review we discuss the key pathogenic and clinical aspects of gallstones, as the main clinical consequences of metabolic dysfunction-associated disease.

Keywords: Bile; Biliary colic; Biliary secretion; CT scan; Cholecystectomy; Cholecystitis; Choledocholithiasis; Cholesterol crystallization; ERCP; MRCP.

Fig. 1

Ultrasonographic study of the gallbladder in the fasting subjects using a 3.5 MHz probe and the longitudinal scan. In the normal gallbladder the content in the lumen (bile) is totally anechoic (i.e., gallstone free and sludge free). The gallbladder wall is slightly hyperechogenic and less than 3 mm thick. The gallbladder has a length of ~ 90 mm and depth of ~ 22 mm. By assuming that width is same size of depth, the fasting gallbladder volume is estimated to be 22.8 mL (ellipsoid formula). In cholecystolithiasis the longitudinal scan shows at least 2 hyperechoic rounded spots each ~ 5–6 mm in size and layering on the distal gallbladder wall. The spots are mobile and gravity dependent at real-time examination and represent stones. The anechoic shadow departs from the distal border of the stones due to posterior attenuation of the ultrasonographic beam

Fig. 2

Cholecystolithiasis. A freshly excised gallbladder after laparoscopic cholecystectomy is cut longitudinally to show hundreds of multifaceted stones. Stones are 0.5–0.8 mm in size. The green colour of the stones depends on the surrounding dark green bile. The chemical analysis of the stones showed pure cholesterol content. With permission from Portincasa P, Wang DQH. Gallstones. In Podolsky KD, Camilleri M, Fitz JG, Kalloo AN, Shanahan F, Wang TC, eds. Yamada’s Atlas of Gastroenterology. 5th ed. Hoboken, New Jersey (USA) Wiley-Blackwell, 2016:335–353 [92]

Fig. 3

Appearance of human gallbladder stones. A Pure cholesterol stones have white colour and a spherical shape with rough surface. B The cut surface of the stone shows a radial crystalline structure with made of pure cholesterol. The black horizontal line is equal to 1 cm. C Multiple stones have multifaceted shape with a smooth surface. D Mixed cholesterol stones are fragmented to show a central pigment structure (brownish) made of calcium bilirubinate surrounded by the cholesterol crystalline structure. E Pure black pigment stones have spherical shape and and show debris which are are soft and easily friable. Panel C with permission from Portincasa P, Wang DQH. Gallstones. In Podolsky KD, Camilleri M, Fitz JG, Kalloo AN, Shanahan F, Wang TC, eds. Yamada’s Atlas of Gastroenterology. 5th ed. Hoboken, New Jersey (USA) Wiley-Blackwell, 2016:335–353 [92]

Fig. 4

A Equilibrium phase diagram of cholesterol–phospholipid (lecithin)–mixed bile salt system at 37 °C, 0.15 M NaCl, pH 7.0, total lipid concentration 7.5 g/dL. The ternary phase diagram depicts positions and configuration of crystallization regions, with components expressed in moles percent. The green one-phase (θ) micellar zone at the bottom of the diagram is enclosed by a solid angulated line. Above, two solid lines divide the two-phase zones from a central three-phase zone. Studies based on the solid and liquid crystallization sequences present in the bile, the left two-phase and central three-phase regions can be divided by dashed lines into regions A, B, C, D, and E. The number of phases given represents the equilibrium state. The phases host cholesterol monohydrate crystals and saturated micelles in the crystallization regions A and B; cholesterol monohydrate crystals, saturated micelles, and liquid crystals in the regions C and D; and liquid crystals of variable composition and saturated micelles for region E. Decreasing total lipid concentration (7.5 g/dL → 2.5 g/dL), bile salt hydrophobicity (3α,12α → 3α,7α → 3α,7α,12α → 3α,7β hydroxylated taurine conjugates), and temperature (37 °C → 4 °C) have profound effect on the crystallization process, since progressively shift all crystallization pathways to lower phospholipid contents, retard crystallization, and reduce micellar cholesterol solubilities. Such changes generate a series of new condensed-phase diagrams with an enlarged region E. Adapted from Wang and Carey [47] and Portincasa and Wang [6, 92]. B Polarizing light microscopy of cholesterol crystals in human gallbladder bile and in model bile. Human bile harvests mature refringent plate-like rectangular cholesterol monohydrate crystals which grow as plates (PL) and aggregates (AG). Typical plates have 79.2° and 100.8° angles. In model bile supersaturated with cholesterol, crystal have grown and are observed in the Bürker cell counting chamber. The solution is populated by several types of cholesterol crystals refringent at microscopy. A, arcs; N, needles; T, tubules are anhydrous crystals. PL, plates and AG, aggregates are mature monohydrate crystals. The black horizontal lines are 200 μm. After D.Q.-H. Wang and M.C. Carey [47] and P. Portincasa, K. J. van Erpecum, A. Jansen, W. Renooij, M. Gadellaa and G. P. vanBerge-Henegouwen [51]

Fig. 5

Management of acute calculous cholecystitis according to Tokyo guidelines [126]. See text for details

Fig. 6

Definition of severity of acute cholangitis